Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn

ABSTRACT

Described herein are unit oral dose compositions that reduce the severity of heartburn and/or the risk of the occurrence of heartburn in a human in need of taking ibuprofen for the OTC treatment of acute pain wherein the human is not experiencing heartburn prior to the oral administration of the unit oral dose composition comprising orally administering to the human of a unit oral dose composition comprising (i) ibuprofen at a dosage from about 50 mg to about 400 mg per unit oral dose composition and (ii) famotidine at a dosage from about 3 mg to about 20 mg per unit oral dose composition, wherein the dissolution rate of famotidine in the unit oral dose composition in said human at a specified time within 45 minutes of administration of said unit oral dose composition to said human is greater than the dissolution rate of ibuprofen in the unit oral dose composition in said human at the same specified time.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Nonprovisionalpatent application Ser. No. 17/375,049, filed on Jul. 14, 2021, whichclaims the benefit of and priority to co-pending U.S. Provisional PatentApplication No. 63/052,398, filed on Jul. 15, 2020, the contents ofwhich are incorporated by reference herein in their entireties.

BACKGROUND

While generally regarded as safe, effective treatments for acute painand fever, the use of non-prescription-strength, or over-the-counter(OTC), non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen canbe associated with stomach problems such as heartburn. In fact, thepackage labeling approved by the U.S. Food and Drug Administration forOTC NSAIDs, including ibuprofen, draws attention to “stomach problemssuch as heartburn” and advises consumers to “take with food or milk ifstomach upset occurs.”

SUMMARY

Described herein are unit oral dose compositions that reduce theseverity of heartburn or the risk of the occurrence of heartburn in ahuman in need of taking ibuprofen for the OTC treatment of acute painwherein the human is not experiencing heartburn prior to the oraladministration of the unit oral dose composition comprising orallyadministering to the human of a unit oral dose composition comprising(i) ibuprofen at a dosage from about 50 mg to about 400 mg per unit oraldose composition and (ii) famotidine at a dosage from about 3 mg toabout 20 mg per unit oral dose composition, wherein the dissolution rateof famotidine in the unit oral dose composition in said human at aspecified time within 45 minutes of administration of said unit oraldose composition to said human is greater than the dissolution rate ofibuprofen in the unit oral dose composition in said human at the samespecified time.

Other advantages of the present disclosure will be or become apparent toone with skill in the art upon examination of the following detaileddescription. It is intended that all such additional advantages beincluded within this description, be within the scope of the presentdisclosure, and be protected by the accompanying claims. In addition,all optional and preferred features and modifications of the describedembodiments are usable in all aspects of the disclosure taught herein.Furthermore, the individual features of the dependent claims, as well asall optional and preferred features and modifications of the describedembodiments are combinable and interchangeable with one another.

DETAILED DESCRIPTION

Before the present compounds, compositions, articles, devices, and/ormethods are disclosed and described, it is to be understood that theaspects described below are not limited to specific compounds, syntheticmethods, or uses as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure.

Any recited method can be carried out in the order of events recited orin any other order that is logically possible. That is, unless otherwiseexpressly stated, it is in no way intended that any method or aspect setforth herein be construed as requiring that its steps be performed in aspecific order. Accordingly, where a method claim does not specificallystate in the claims or descriptions that the steps are to be limited toa specific order, it is no way intended that an order be inferred, inany respect. This holds for any possible non-express basis forinterpretation, including matters of logic with respect to arrangementof steps or operational flow, plain meaning derived from grammaticalorganization or punctuation, or the number or type of aspects describedin the specification.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited. The publications discussed herein areprovided solely for their disclosure prior to the filing date of thepresent application. Nothing herein is to be construed as an admissionthat the present invention is not entitled to antedate such publicationby virtue of prior invention. Further, the dates of publication providedherein can be different from the actual publication dates, which canrequire independent confirmation.

While aspects of the present disclosure can be described and claimed ina particular statutory class, such as the system statutory class, thisis for convenience only and one of skill in the art will understand thateach aspect of the present disclosure can be described and claimed inany statutory class.

It is also to be understood that the terminology used herein is for thepurpose of describing particular aspects only and is not intended to belimiting. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art to which the disclosed compositions andmethods belong. It will be further understood that terms, such as thosedefined in commonly used dictionaries, should be interpreted as having ameaning that is consistent with their meaning in the context of thespecification and relevant art and should not be interpreted in anidealized or overly formal sense unless expressly defined herein.

Prior to describing the various aspects of the present disclosure, thefollowing definitions are provided and should be used unless otherwiseindicated. Additional terms may be defined elsewhere in the presentdisclosure.

Definitions

As used herein, “comprising” is to be interpreted as specifying thepresence of the stated features, integers, steps, or components asreferred to, but does not preclude the presence or addition of one ormore features, integers, steps, or components, or groups thereof.Moreover, each of the terms “by”, “comprising,” “comprises”, “comprisedof,” “including,” “includes,” “included,” “involving,” “involves,”“involved,” and “such as” are used in their open, non-limiting sense andmay be used interchangeably. Further, the term “comprising” is intendedto include examples and aspects encompassed by the terms “consistingessentially of” and “consisting of.” Similarly, the term “consistingessentially of” is intended to include examples encompassed by the term“consisting of.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an inert excipient”includes, but are not limited to, mixtures or combinations of two ormore such inert excipients, and the like.

It should be noted that ratios, concentrations, amounts, rates, andother numerical data can be expressed herein in a range format. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. Ranges can be expressed herein as from “about” one particularvalue, and/or to “about” another particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms a furtheraspect. For example, if the value “about 10” is disclosed, then “10” isalso disclosed and “about 5 to about 15” is also disclosed.

When a range is expressed, a further aspect includes from the oneparticular value and/or to the other particular value. For example,where the stated range includes one or both of the limits, rangesexcluding either or both of those included limits are also included inthe disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to‘y’ as well as the range greater than ‘x’ and less than ‘y’. The rangecan also be expressed as an upper limit, e.g. ‘about x, y, z, or less’and should be interpreted to include the specific ranges of ‘about x’,‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, lessthan y′, and ‘less than z’. Likewise, the phrase ‘about x, y, z, orgreater’ should be interpreted to include the specific ranges of ‘aboutx’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’,greater than y′, and ‘greater than z’. In addition, the phrase “about‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’to about ‘y’”.

It is to be understood that such a range format is used for convenienceand brevity, and thus, should be interpreted in a flexible manner toinclude not only the numerical values explicitly recited as the limitsof the range, but also to include all the individual numerical values orsub-ranges encompassed within that range as if each numerical value andsub-range is explicitly recited. To illustrate, a numerical range of“about 0.1% to 5%” should be interpreted to include not only theexplicitly recited values of about 0.1% to about 5%, but also includeindividual values (e.g., about 1%, about 2%, about 3%, and about 4%) andthe sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%;about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and otherpossible sub-ranges) within the indicated range.

As used herein, the terms “about,” “approximate,” “at or about,” and“substantially” mean that the amount or value in question can be theexact value or a value that provides equivalent results or effects asrecited in the claims or taught herein. That is, it is understood thatamounts, sizes, formulations, parameters, and other quantities andcharacteristics are not and need not be exact, but may be approximateand/or larger or smaller, as desired, reflecting tolerances, conversionfactors, rounding off, measurement error and the like, and other factorsknown to those of skill in the art such that equivalent results oreffects are obtained. In some circumstances, the value that providesequivalent results or effects cannot be reasonably determined. In suchcases, it is generally understood, as used herein, that “about” and “ator about” mean the nominal value indicated ±10% variation unlessotherwise indicated or inferred. In general, an amount, size,formulation, parameter or other quantity or characteristic is “about,”“approximate,” or “at or about” whether or not expressly stated to besuch. It is understood that where “about,” “approximate,” or “at orabout” is used before a quantitative value, the parameter also includesthe specific quantitative value itself, unless specifically statedotherwise.

It should be noted that ratios, concentrations, amounts, rates, andother numerical data can be expressed herein in a range format. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. Ranges can be expressed herein as from “about” one particularvalue, and/or to “about” another particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms a furtheraspect. For example, if the value “about 10” is disclosed, then “10” isalso disclosed.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B—F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceand instances where it does not.

“Famotidine” is3-[2-(diaminomethyleneamino)thiazol-4-ylmethylthio]-N-sulfamoylpropionamidine,including polymorphic forms such as those designated Form A and Form B(see, e.g., U.S. Pat. Nos. 5,128,477 and 5,120,850) and their mixtures.

“Ibuprofen” is isobutylphenylpropionic acid. Examples of suitable formsof ibuprofen include, but are not limited to racemic ibuprofen,(S)-ibuprofen, or (R)-ibuprofen. In one aspect, (S)-ibuprofen can besynthesized from racemic ibuprofen using techniques known in the art(Enzyme and Microbial Technology, Vol. 24, Issues 3-4, pp 160-163(1999)).

As used herein, “unit oral dose composition” refers to physicallydiscrete units suitable for use in a human, each unit containing apredetermined quantity of famotidine and a predetermined quantity ofibuprofen calculated to produce the desired response or responses inassociation with its administration.

The term “immediate-release” or “immediate release” refers to therelease of famotidine and/or ibuprofen quickly after oral administrationof the unit dose composition to the human.

As used herein, “treatment regimen” refers to the administration of theunit oral dose composition at the same dosage to a human over a periodof time. For example, a human may initially be administered two tabletsof the unit oral dose composition, then administered two tablets of theunit oral dose composition 6 hours later, for a maximum total of 4tablet unit oral dose compositions over a 24-hour period. In one aspect,a human may initially be administered one tablet of the unit oral dosecomposition, then administered one tablet of the unit oral dosecomposition 6 hours later, for a maximum total of 3 tablet unit oraldose compositions over a 24-hour period. In another aspect, a human mayinitially be administered two tablets of the unit oral dose composition,then administered two tablets of the unit oral dose composition 4 hourslater, then administered one tablet of the unit oral dose composition 4hours later, for a maximum total of 5 tablet unit oral dose compositionsover a 24-hour period.

The term “heartburn” is also known as pyrosis, cardialgia or acidindigestion. Symptoms of heartburn include, but are not limited to, aburning sensation in the central chest or upper central abdomen, whichcan be a source of pain to the subject. The pain or discomfort oftenrises in the chest and may radiate to the neck, angle of the arm, orthroat, leaving a sour, acidic or salty taste in the back of the throat.Heartburn is usually due to regurgitation of gastric acid (gastricreflux) into the esophagus and is the major symptom of gastroesophagealreflux disease (GERD). Heartburn can be caused by hiatal hernia,pregnancy, being overweight or a smoker, certain medications (e.g.,NSAIDs like ibuprofen, naproxen sodium, acetylsalicylic acid), largemeals, certain foods (such as onions or citrus fruits), lying down witha full stomach, stress, etc.

The term “treat or treatment” as used herein is defined as reducing theoccurrence and/or severity of one or more symptoms when the human isadministered a unit oral dose composition as described herein whencompared to the same symptom(s) in the absence of the administration ofthe unit oral dose composition to the human, specifically, preventingthe occurrence of ibuprofen-induced heartburn and/or reducing theseverity of ibuprofen-induced heartburn.

The term “prevent or prevention” as used herein is defined aseliminating or reducing the likelihood, or risk, of the occurrenceand/or severity of one or more symptoms when the human is administered aunit oral dose composition as described herein when compared to the samesymptom(s) in the absence of the administration of the unit oral dosecomposition to the human.

The term “acute pain” is pain that is not persistent, generally lasts abrief period of time (e.g., hours, 1-3 days, 1 week), and is resolvedquickly. Examples of acute pain include, but are not limited to, acutepain of inflammation (including menstrual cramps, or dysmenorrhea),acute pain or stiffness of rheumatic or arthritic conditions (“flares”of osteoarthritis), minor pain of arthritis, acute joint and body pains,acute muscular aches and strains, acute pain of ligamentous sprains(including sprained ankle), acute backache, minor aches and pains due tothe common cold (including acute sore throat of infectious ornon-infectious origin and sinus pain), minor aches and pains due tofever (including muscle achiness, or myalgia), acute headache (includingacute tension-type and migraine), acute pain of minor surgery (includingacute pain of dental extractions), acute toothache, occasionalsleeplessness when associated with minor aches and pains, or anycombination thereof.

The term “chronic pain” is pain that is persistent, generally lasts morethan three months, up to years, and is not resolved quickly. An exampleof chronic pain includes pain caused by cancer or by metastases ofcancer throughout the body, in particular, to bones. Other examplesinclude chronic non-malignant pain, chronic neurologic diseases such asnerve impingement, spinal stenosis and other skeletal diseases of theback and limbs, chronic arthritis such as osteoarthritis, rheumatoidarthritis and psoriatic arthritis, chronic arthritis due to autoimmunediseases, fibromyalgia, etc.

As used herein, “effective amount” can refer to the amount of adisclosed compound or pharmaceutical composition provided herein that issufficient to effect beneficial or desired biological, emotional,medical, or clinical response of a cell, tissue, system, animal, orhuman. An effective amount can be administered in one or moreadministrations, applications, or dosages. The term can also includewithin its scope amounts effective to enhance or restore tosubstantially normal physiological function or clinical response.

As used herein, the term “therapeutically effective amount” refers to anamount that is sufficient to achieve the desired therapeutic result orto have an effect on undesired symptoms. The specific therapeuticallyeffective dose level for any particular subject will depend upon avariety of factors including the disorder or condition being treated andthe severity of the disorder or condition; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the time of administration; the time since eating solid food;drinking milk; the route of administration; the rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed and likefactors which may be well known in the medical arts. In the case oftreating a particular disorder or condition, in some instances, thedesired response can be inhibiting a worse progression of the disorderor condition, reducing the severity of the disorder or condition. Thedesired response to treatment of the disorder or condition also can bedelaying the onset or even preventing the onset of the disorder orcondition.

As used herein, the term “human” refers to any subject that isexperiencing acute pain in need of pain relief. The age of the human isthe age range suitable for administering ibuprofen and famotidine. Thus,“human” as used herein includes adults and children of age that can takefamotidine and ibuprofen individually.

The unit oral dose compositions described herein treat acute pain whilereducing the occurrence and/or severity of heartburn induced by theshort-term use of OTC (not prescription-strength) ibuprofen. The unitoral dose compositions described herein are not intended for thetreatment of chronic pain. In another aspect, the unit oral dosecomposition further provides enhanced fever reduction and relief offever-associated aches and pains in a human when compared to theadministration to said human of the same dosage strength of saidibuprofen in the absence of said famotidine.

The dosage of ibuprofen and famotidine in the unit oral dosecompositions described herein can vary. In one aspect, ibuprofen is fromabout 50 mg to about 400 mg per unit oral dose composition, or about 50mg, 75 mg, 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, 200 mg, 220mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 300 mg, 320 mg, 330 mg, 340mg, 360 mg, 380 mg, or 400 mg where any value can be a lower and upperendpoint of a range (e.g., about 200 mg to about 250 mg). In anotheraspect, ibuprofen is about 250 mg per unit oral dose composition. In oneaspect, ibuprofen is about 200 mg per unit oral dose composition. Inanother aspect, ibuprofen is about 150 mg per unit oral dosecomposition. In another aspect, ibuprofen is about 100 mg per unit oraldose composition.

In one aspect, famotidine is from about 3 mg to about 20 mg per unitoral dose composition, or about 3 mg, 5 mg, 6.67 mg, 10 mg, 13.33 mg, 15mg, 20 mg, where any value can be a lower and upper endpoint of a range(e.g., about 10 mg to about 20 mg). In one aspect, famotidine is about3.33 mg, about 5 mg, about 6.67 mg, about 10 mg, or about 13.33 mg perunit oral dose composition.

In one aspect, ibuprofen is from about 133 mg to about 400 mg per unitoral dose composition and famotidine is from about 3 mg to about 20 mgper unit oral dose composition. In another aspect, ibuprofen is about200 mg per unit oral dose composition and famotidine is from about 3 mgto about 10 mg per unit oral dose composition. In another aspect,ibuprofen is about 200 mg per unit oral dose composition and famotidineis about 3.33 mg or about 6.67 mg per unit oral dose composition. Inanother aspect, ibuprofen is about 200 mg per unit oral dose compositionand famotidine is about 10 mg per unit oral dose composition. In anotheraspect, ibuprofen is about 200 mg per unit oral dose composition andfamotidine is about 13.33 mg per unit oral dose composition. In anotheraspect, ibuprofen is from about 100 mg to about 400 mg per unit oraldose composition and famotidine is about 3.33 mg to about 13.33 mg perunit oral dose composition. In another aspect, ibuprofen is from about100 mg to about 400 mg per unit oral dose composition and famotidine isabout 6.67 mg per unit oral dose composition. In another aspect,ibuprofen is from about 133 mg to about 150 mg per unit oral dosecomposition and famotidine is about 6.67 mg to about 10 mg per unit oraldose composition. In another aspect, ibuprofen is from about 150 mg toabout 220 mg per unit oral dose composition and famotidine is about 3.33mg to about 5 mg per unit oral dose composition. In another aspect,ibuprofen is from about 150 mg to about 220 mg per unit oral dosecomposition and famotidine is about 6.67 mg per unit oral dosecomposition. In another aspect, ibuprofen is about 250 mg per unit oraldose composition and famotidine is about 10 mg or about 13.33 mg perunit oral dose composition.

In other aspects, the unit oral dose compositions can include otherbioactive agents. In one aspect, the unit oral dose composition furthercomprises a non-NSAID (nonsteroidal anti-inflammatory drug) for reliefof acute pain and reduction of fever. In one aspect, the unit oral dosecomposition further comprises a non-NSAID such as, for example,acetaminophen, preferably at a 5:3 or 3:2 ratio of the NSAID (e.g.,ibuprofen) to the non-NSAID (e.g., acetaminophen). In one aspect, the anon-NSAID is at a dosage of about 50 mg to about 500 mg, or about 50 mg,60 mg, 65 mg, 66.67 mg, 70 mg, 75 mg, 80 mg, 85 mg, 88.67 mg, 90 mg, 100mg, 125 mg, 133.34 mg, 150 mg, 160 mg, 166.67 mg, 200 mg, 225 mg, 250mg, 300 mg, 325 mg, 375 mg, 400 mg, 450 mg, or 500 mg, where any valuecan be a lower and upper endpoint of a range (e.g., about 100 mg toabout 200 mg or about 325 mg to about 500 mg). In another aspect, thenon-NSAID is acetaminophen at a dosage of about 150 mg. In anotheraspect, ibuprofen is about 250 mg combined with acetaminophen about 250mg per unit oral dose composition and famotidine is about 10 mg or about13.33 mg per unit oral dose composition. In another aspect, ibuprofen isabout 250 mg combined with acetaminophen about 325 mg or about 500 mgper unit oral dose composition and famotidine is about 10 mg or about13.33 mg per unit oral dose composition. In another aspect, ibuprofen isabout 200 mg combined with acetaminophen about 250 mg per unit oral dosecomposition and famotidine is about 10 mg or about 13.33 mg per unitoral dose composition. In another aspect, ibuprofen is about 200 mgcombined with acetaminophen about 325 mg or about 500 mg per unit oraldose composition and famotidine is about 10 mg to about 13.33 mg perunit oral dose composition. In another aspect, ibuprofen is from about150 mg to about 220 mg per unit oral dose composition combined withacetaminophen about 250 mg to about 500 mg per unit oral dosecomposition and famotidine is about 6.67 mg to about 13.33 mg per unitoral dose composition.

In one aspect, when the unit oral dose composition includesacetaminophen, the unit oral dose composition further provides enhancedand/or earlier pain reduction in the human when compared to the oraladministration to the human of the same dosage strength of ibuprofen inthe absence of acetaminophen and famotidine. In one aspect, the unitoral dose composition with acetaminophen can provide enhanced feverreduction when compared to the oral administration to the human of thesame dosage strength of ibuprofen in the absence of acetaminophen andfamotidine.

In another aspect, the unit oral dose composition (containingacetaminophen or not containing acetaminophen) further comprises a sleepaid for relief of occasional sleeplessness associated with minor achesand pains. In one aspect, the unit oral dose composition furthercomprises a sleep aid such as, for example, diphenhydramine HCl. In oneaspect, the sleep aid is at a dosage of about 5 mg to about 50 mg, orabout 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45mg, or 50 mg, where any value can be a lower and upper endpoint of arange (e.g., about 35 mg to about 40 mg). In another aspect, the sleepaid is diphenhydramine citrate at a dosage of about 12.5 mg.

In one aspect, when the unit oral dose composition includesdiphenhydramine HCl or diphenhydramine citrate, the unit oral dosecomposition further provides enhanced pain reduction in the human whencompared to the oral administration to the human of the same dosagestrength of ibuprofen in the absence of diphenhydramine, acetaminophenand famotidine. In one aspect, the unit oral dose composition withdiphenhydramine HCl or diphenhydramine citrate can provide enhancednighttime acute pain reduction for less awakening and increased durationof sleep, not disturbed by pain.

The unit oral dose compositions described herein can be formulated aspharmaceutical compositions for oral administration. In one aspect, theunit oral dose compositions can be in the form of solid dosage forms(i.e., unit oral solid dose composition) such as, for example, tablets,capsules, caplets, gelcaps, geltabs, pills, lozenges, chewable articles(e.g., a gummy), dissolvable strips (e.g., placement under the tongue),or any other suitable form for oral administration. In one aspect, theunit oral solid dose compositions can be oval-shaped or spherical-shapedforms such as tablets, capsules, caplets, gelcaps, geltabs, pills,lozenges, chewable articles (e.g., a gummy), etc. In another aspect, theunit oral dose compositions can be in the form of solid dosage formswhich are on the exterior blue or blue-purple color, purple or violetcolor, deep blue or sea-blue, denim blue, colonial blue, brown, or tanor shades of blue, deep blue, blue/purple, sea-blue, purple or violetcolor, denim blue, colonial blue, brown (such as mocha, pecan, tortilla,caramel, cinnamon) or tan (such as beige, ecru, cream, sand, stone,Khaki or British tan), with light brown speckles or dots.

In addition to ibuprofen and famotidine, the unit oral dose compositionscan include one or more pharmaceutically-acceptable carriers. As usedherein, “pharmaceutically-acceptable carriers” means one or more of apharmaceutically acceptable diluents, preservatives, antioxidants,solubilizers, emulsifiers, coloring agents, releasing agents, coatingagents, sweetening, perfuming agents, and adjuvants. The disclosedpharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy and pharmaceutical sciences.

In one aspect, the unit oral dose compositions can be formulated with aflavoring agent. The flavoring agent can improve the desirablecharacteristics of taste, texture, and overall palatability of the unitoral dose compositions. The flavoring agent can be formulated with theunit oral dose composition in a number of different ways. In one aspect,the flavoring agent is admixed with ibuprofen and/or famotidine alongwith one or more pharmaceutically acceptable carriers. In anotheraspect, the unit oral dose composition is spray-coated with a very thinfilm of the flavoring agent. Examples of flavoring agents useful hereininclude, but are not limited to, almond oil, vanillin, menthol,I-menthol, peppermint spirit, peppermint oil (liquid or solid), or anycombination thereof.

The unit oral dose compositions can include one or more pharmaceuticalexcipients and/or additives. Non-limiting examples of suitableexcipients and additives include magnesium stearate, titanium dioxide,red iron oxide, yellow iron oxide, gelatin, natural sugars such as rawsugar or lactose, non-sugar sweeteners (e.g., aspartame, acesulfamepotassium, luo han guo (monk) fruit extract, neotame, saccharin, stevia,sucralose and advantame), lecithin, pectin, starches (for example cornstarch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate,gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (forexample colloidal), cellulose, cellulose derivatives (for examplecellulose ethers in which the cellulose hydroxy groups are partiallyetherified with lower saturated aliphatic alcohols and/or lowersaturated, aliphatic oxyalcohols, for example methyl oxypropylcellulose, methyl cellulose, hydroxypropyl methyl cellulose,hydroxypropyl methyl cellulose phthalate, microcrystalline cellulose),fatty acids as well as magnesium, calcium or aluminum salts of fattyacids with 12 to 22 carbon atoms, in particular saturated (for examplestearates), emulsifiers, oils and fats, in particular vegetable (forexample, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil,corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in eachcase also optionally hydrated); glycerol esters and polyglycerol estersof saturated fatty acids C12H2402 to 018H3602 and their mixtures, itbeing possible for the glycerol hydroxy groups to be totally or alsoonly partly esterified (for example mono-, di- and triglycerides);pharmaceutically acceptable mono- or multivalent alcohols andpolyglycols such as polyethylene glycol and derivatives thereof, estersof aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms,in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol,diethylene glycol, pentacrythritol, sorbitol, mannitol and the like,which may optionally also be etherified, esters of citric acid withprimary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes,glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with01-012-alcohols, dimethylacetamide, lactamides, and the like.

Other auxiliary substances useful in preparing the unit oral dosecompositions are those which cause disintegration (so-calleddisintegrants), such as: cross-linked polyvinyl pyrrolidone, sodiumcarboxymethyl starch, sodium carboxymethyl cellulose or microcrystallinecellulose. Conventional coating substances may also be used to producethe oral dosage form. Those that may for example be considered are:polymerizates as well as copolymerizates of acrylic acid and/ormethacrylic acid and/or their esters; copolymerizates of acrylic andmethacrylic acid esters with a lower ammonium group content (for examplesold under the trademark EUDRAGIT® RS), copolymerizates of acrylic andmethacrylic acid esters and trimethyl ammonium methacrylate (for examplesold under the trademark EUDRAGIT® RL); polyvinyl acetate; fats, oils,waxes, carnauba wax, fatty alcohols; hydroxypropyl methyl cellulosephthalate or acetate succinate; cellulose acetate phthalate, starchacetate phthalate as well as polyvinyl acetate phthalate, carboxy methylcellulose; methyl cellulose phthalate, methyl cellulose succinate,-phthalate succinate as well as methyl cellulose phthalic acid halfester; zein; ethyl cellulose as well as ethyl cellulose succinate;shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acidanhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer;styrol-maleic acid copolymerizate; 2-ethyl-hexyl-acrylate maleic acidanhydride; crotonic acid-vinyl acetate copolymer; glutaminicacid/glutamic acid ester copolymer; carboxymethylethylcellulose glycerolmonooctanoate; cellulose acetate succinate; polyarginine.

Plasticizing agents that may be considered as coating substances withthe unit oral dose compositions citric and tartaric acid esters (acetyltriethyl citrate, acetyl tributyl citrate, triethyl citrate); glyceroland glycerol esters (glycerol diacetate, -triacetate, acetylatedmonoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-,diethyl-, dimethyl-, dipropyl-phthalate), di-(2-methoxy- or2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethylglycolate and butylglycolate; alcohols (propylene glycol, polyethyleneglycol of various chain lengths), adipates (diethyladipate,di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl- anddiburylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycoldipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate;tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate(polysorbates such as polysorbate 50); sorbitan monooleate.

Moreover, suitable binders, lubricants, disintegrating agents, coloringagents, flavoring agents, flow-inducing agents, and melting agents maybe included as carriers. The pharmaceutical carrier employed can be, forexample, a solid, liquid, or gas. Examples of solid carriers include,but are not limited to, lactose, terra alba, sucrose, glucose,methylcellulose, dicalcium phosphate, calcium sulfate, mannitol,sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesiumstearate, and stearic acid. Examples of liquid carriers are sugar syrup,peanut oil, olive oil, and water. Examples of gaseous carriers includecarbon dioxide and nitrogen.

In various aspects, a binder can include, for example, starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners,hypromellose, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium acetate, sodium chloride,and the like. In a further aspect, a disintegrator can include, forexample, starch, methyl cellulose, sodium starch glycolate, agar,bentonite, xanthan gum, and the like.

In certain aspects, the unit oral dose compositions are formulated suchthat famotidine is released at a greater rate than ibuprofen. In oneaspect, a disintegrant or diluent can be admixed with famotidinefollowed by formulation with ibuprofen to produce the unit oral dosecomposition. In another aspect, the unit oral dose composition caninclude different disintegrants or diluents in order to releasefamotidine first followed by ibuprofen (e.g, famotidine is admixed witha first disintegrant and ibuprofen is admixed with a seconddisintegrant). In another aspect, when the same disintegrant is used,the amount of disintegrant admixed with famotidine can be greater thanthe amount of disintegrant admixed with ibuprofen.

In one aspect, the unit oral dose composition includes microparticlesand/or nanoparticles of famotidine. In certain aspects, the unit oraldose composition is composed of a first population of microparticlescomposed of famotidine and a second population of microparticlescomposed of ibuprofen. In one aspect, the particle size of the firstpopulation of microparticles is different than the particle size of thesecond population of microparticles. In another aspect, the firstpopulation of microparticles is composed of a different material thanthe second population of microparticles. By varying the particle sizeand composition of the first and second population of microparticles, itis possible to vary the dissolution rate of each population ofmicroparticles.

In another aspect, the unit oral dose composition includesmicroparticles and/or nanoparticles of famotidine. In certain aspects,the unit oral dose composition is composed of a first population ofmicroparticles composed of famotidine, a second population ofmicroparticles composed of ibuprofen, and a third population ofmicroparticles composed of acetaminophen. In one aspect, the particlesize of the first population of microparticles is different than theparticle size of the second population of microparticles. In anotheraspect, the particle size of the second population of microparticles isdifferent than the particle size of the third populations ofmicroparticles. In another aspect, the first population ofmicroparticles is composed of a different material than the secondpopulation of microparticles. In another aspect, the second populationof microparticles is composed of a different material than the thirdpopulation of microparticles. By varying the particle size andcomposition of the first, second and third population of microparticles,it is possible to vary the dissolution rate of each population ofmicroparticles.

In one aspect, the microparticles can be manufactured by traditionaltechniques based on friction such as, for example, milling or grinding(e.g., spiral jet milling, fluid bed jet milling). In another aspect,the microparticles can be manufactured by precipitation from saturatedor super saturated solutions, spray drying, or in situ micronization(Hovione) methods. In other aspects, supercritical fluids can be used toproduce the micronized particles useful herein. Techniques such as, forexample, Rapid Expansion of Supercritical Solutions (RESS),Supercritical Anti-Solvent (SAS), Particles from Gas Saturated Solutions(PGSS) use supercritical fluids to produce micronized particles. USPublication Nos. 2021/0106511 and 2021/0060268, which are incorporatedby reference in their entireties, provides non-limiting techniques forproducing microparticles for the oral delivery of therapeutic agents. Inone aspect, microparticles of famotidine can have an average particlediameter of from about 1 μm to about 1,000 μm, or about 1 μm, 10 μm, 20μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 500 μm, 550 μm, 600μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, or 1,000 μm,where any value can be a lower and upper endpoint of a range (e.g., 10μm to 100 μm).

In other aspects, the unit oral dose compositions can be formulated withnanoparticles to produce rapidly dissolving oral formulations. In oneaspect, polymers (e.g., polysaccharides such as amylopectin, starch,glycogen, cellulose, dextrin, chitin, alpha glucan, beta glucan, andcombinations thereof) or inorganic materials (e.g., inert silica) can beadmixed with famotidine and ibuprofen followed by the production ofnanoparticles using techniques known in the art such as, for example,ionotropc gelation or spray-drying. US Publication No. 2015/0147399,which is incorporated by reference in its entirety, providesnon-limiting techniques for producing nanoparticles for the oraldelivery of therapeutic agents.

In one aspect, nanoparticles of famotidine can have an average particlediameter of from about 1 nm to about 1,000 nm, or about 1 nm, 10 nm, 20nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 150 nm, 200nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 500 nm, 550 nm, 600nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, or 1,000 nm,where any value can be a lower and upper endpoint of a range (e.g., 10nm to 100 nm).

In certain aspects, the unit oral dose composition is composed a firstpopulation of nanoparticles composed of famotidine and a secondpopulation of nanoparticles composed of ibuprofen. In one aspect, theparticle size of the first population of nanoparticles is different thanthe particle size of the second population of nanoparticles. In anotheraspect, the first population of nanoparticles is composed of a differentmaterial than the second population of nanoparticles. By varying theparticle size and composition of the first and second population ofnanoparticles, it is possible to vary the dissolution rate of eachpopulation of nanoparticles.

In certain aspects, the unit oral dose composition is composed of afirst population of nanoparticles composed of famotidine, a secondpopulation of nanoparticles composed of ibuprofen, and a thirdpopulation of nanoparticles composed of acetaminophen. In one aspect,the particle size of the first population of nanoparticles is differentthan the particle size of the second population of nanoparticles. Inanother aspect, the particle size of the second population ofnanoparticles is different than the particle size of the thirdpopulation of nanoparticles. In another aspect, the first population ofnanoparticles is composed of a different material than the secondpopulation of nanoparticles. In another aspect, the second population ofnanoparticles is composed of a different material than the thirdpopulation of nanoparticles. By varying the particle size andcomposition of the first, second and third population of nanoparticles,it is possible to vary the dissolution rate of each population ofnanoparticles.

In one aspect, the unit oral dose composition is composed a firstpopulation of nanoparticles composed of (1) famotidine with inertingredients such as, for example, hydroxypropyl cellulose, hypromellose,iron oxides, magnesium stearate, microcrystalline cellulose, cornstarch, talc, titanium dioxide, and carnauba wax, and any combinationthereof and (2) a second population of nanoparticles composed ofibuprofen with inert ingredients such as, for example, gelatin,glycerin, hypromellose, lactic acid, mannitol, polyethylene glycol,povidone, propylene glycol, sorbitan, sorbitol, titanium dioxide, or anycombination thereof.

In another aspect, the unit oral dose composition is composed a firstpopulation of nanoparticles composed of (1) famotidine with inertingredients such as, for example, hydroxypropyl cellulose, hypromellose,iron oxides, magnesium stearate, microcrystalline cellulose, cornstarch, talc, titanium dioxide, and carnauba wax, and any combinationthereof; (2) a second population of nanoparticles composed of ibuprofenwith inert ingredients such as, for example, gelatin, glycerin,hypromellose, lactic acid, mannitol, polyethylene glycol, povidone,propylene glycol, sorbitan, sorbitol, titanium dioxide, or anycombination thereof; and (3) a third population of nanoparticlescomposed of acetaminophen with inert ingredients such as, for example,hypromellose, magnesium stearate, modified or pregelatinized starch,sodium starch glycolate, powdered or microcrystalline cellulose,propylene glycol, titanium dioxide polysorbate 80, povidone, stearicacid, titanium dioxide, carnauba wax, or any combination thereof.

In one aspect, the average particle size of the ibuprofen is greaterthan average particle size of the famotidine. In one aspect, the averageparticle size of the ibuprofen is 1.5, 2, 2.5, 3, 3, 3.5, 4, 4.5, 5, 6,7, 8, 9, or 10 times greater than the average particle size offamotidine.

In another aspect, the average particle size of the ibuprofen is greaterthan average particle size of the acetaminophen. In one aspect, theaverage particle size of the ibuprofen is 1.5, 2, 2.5, 3, 3, 3.5, 4,4.5, 5, 6, 7, 8, 9, or 10 times greater than the average particle sizeof acetaminophen.

In one aspect, a tablet containing famotidine and ibuprofen can beprepared by compression or molding, optionally with one or moreaccessory ingredients or adjuvants. Compressed tablets can be preparedby compression or pressing machines, where the components are in afree-flowing form such as powder or granules and optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. In oneaspect, the tablet includes microparticles and/or nanoparticles offamotidine.

In another aspect, a bi-layer tablet with a first layer composed offamotidine and a second layer composed of ibuprofen can be formulated asthe unit oral dose composition. In one aspect, the unit oral dosecomposition is a bi-layer tablet composed of (1) a first layer composedof famotidine with inert ingredients such as, for example, hydroxypropylcellulose, hypromellose, iron oxides, magnesium stearate,microcrystalline cellulose, corn starch, talc, titanium dioxide, andcarnauba wax, and any combination thereof and (2) a second layercomposed of ibuprofen with inert ingredients such as, for example,gelatin, glycerin, hypromellose, lactic acid, mannitol, polyethyleneglycol, povidone, propylene glycol, sorbitan, sorbitol, titaniumdioxide, or any combination thereof.

In another aspect, a bi-layer tablet with a first layer composed offamotidine and acetaminophen and a second layer composed of ibuprofencan be formulated as the unit oral dose composition. In one aspect, theunit oral dose composition is a bi-layer tablet composed of (1) a firstlayer composed of famotidine and acetaminophen with inert ingredientssuch as, for example, hydroxypropyl cellulose, hypromellose, ironoxides, magnesium stearate, microcrystalline cellulose, corn starch,talc, titanium dioxide, and carnauba wax, and any combination thereofand (2) a second layer composed of ibuprofen with inert ingredients suchas, for example, gelatin, glycerin, hypromellose, lactic acid, mannitol,polyethylene glycol, povidone, propylene glycol, sorbitan, sorbitol,titanium dioxide, or any combination thereof.

In another aspect, the unit oral dose composition can be formulated as asolid dose spherical- or oval-shaped form, where the core of the soliddose form is composed of ibuprofen surrounded by an outer layer offamotidine. In one aspect, the unit oral dose composition is composed of(1) a first layer composed of famotidine with inert ingredients such as,for example, hydroxypropyl cellulose, hypromellose, iron oxides,magnesium stearate, microcrystalline cellulose, corn starch, talc,titanium dioxide, and carnauba wax, and any combination thereofsurrounding a core composed of (2) ibuprofen with inert ingredients suchas, for example, gelatin, glycerin, hypromellose, lactic acid, mannitol,polyethylene glycol, povidone, propylene glycol, sorbitan, sorbitol,titanium dioxide, or any combination thereof.

In another aspect, the unit oral dose composition can be formulated as asolid dose spherical- or oval-shaped form, where the core of the soliddose form is composed of ibuprofen surrounded by an outer layer offamotidine and acetaminophen. In one aspect, the unit oral dosecomposition is composed of (1) a first layer composed of famotidine andacetaminophen with inert ingredients such as, for example, hydroxypropylcellulose, hypromellose, iron oxides, magnesium stearate,microcrystalline cellulose, corn starch, talc, titanium dioxide, andcarnauba wax, and any combination thereof surrounding a core composed of(2) ibuprofen with inert ingredients such as, for example, gelatin,glycerin, hypromellose, lactic acid, mannitol, polyethylene glycol,povidone, propylene glycol, sorbitan, sorbitol, titanium dioxide, or anycombination thereof.

In one preferred aspect, the unit oral dose composition comprises asolid dosage form, wherein the core of the solid dosage form comprisesibuprofen surrounded by an outer layer of famotidine microparticles. Theibuprofen core may vary in shape and may be, for example, round, ovoid,oblong, convex, cylindrical (e.g., disk shaped) or any other suitablegeometric shape, for example rectilinear. Preferably the tablet has adisk, spherical, rhomboidal, or oval-shape that is ovoid-contoured likea flattened disk or torpedo. The edges of the tablets may be beveled orrounded. The tablet may also be shaped as a caplet (capsule formtablet). The tablets may be scored, embossed or engraved. In oneembodiment, the core does not have an internal hole extending all orpart-way through the pill.

The famotidine layer can be applied to the ibuprofen core usingtechniques known in the art. In one aspect, the famotidine is applied tothe ibuprofen core by compression or spray coating. In one aspect, themethods disclosed in US Publication No. 2019/0307702, which isincorporated by reference in its entirety, provides non-limitingtechniques for producing multiparticulates comprising a melt-congealcore surrounded by a solid amorphous dispersion layer comprising a drugand a polymer. In one aspect, the famotidine layer can have a thicknessof from about 10 μm to about 500 μm, or about 10 μm, 20 μm, 30 μm, 40μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200 μm, 250 μm,300 μm, 350 μm, 400 μm, 450 μm, 500 μm, or 500 μm, where any value canbe a lower and upper endpoint of a range (e.g., 10 μm to 100 μm).

In another aspect, the unit oral dose composition comprises a soliddosage form, wherein the core of the solid dosage form comprisesibuprofen surrounded by an outer layer of famotidine microparticles andacetaminophen particles. The ibuprofen core may vary in shape and maybe, for example, round, ovoid, oblong, convex, cylindrical (e.g., diskshaped) or any other suitable geometric shape, for example rectilinear.Preferably the tablet has a disk, spherical, rhomboidal, or oval-shapethat is ovoid-contoured like a flattened disk or torpedo. The edges ofthe tablets may be beveled or rounded. The tablet may also be shaped asa caplet (capsule form tablet). The tablets may be scored, embossed orengraved. In one embodiment, the core does not have an internal holeextending all or part-way through the pill.

The famotidine and acetaminophen layer can be applied to the ibuprofencore using techniques known in the art. In one aspect, the famotidineand acetaminophen are applied to the ibuprofen core by compression orspray coating. In one aspect, the methods disclosed in US PublicationNo. 2019/0307702, which is incorporated by reference in its entirety,provides non-limiting techniques for producing multi-particulatescomprising a melt-congeal core surrounded by a solid amorphousdispersion layer comprising a drug and a polymer. In one aspect, thefamotidine and acetaminophen layer can have a thickness of from about 10μm to about 500 μm, or about 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm,70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400μm, 450 μm, 500 μm, or 500 μm, where any value can be a lower and upperendpoint of a range (e.g., 10 μm to 100 μm). In another aspect, thefamotidine is applied to the ibuprofen core by compression or spraycoating, and the acetaminophen is applied to the famotidine layer bycompression or spray coating. In one aspect, the famotidine andacetaminophen layers can have a thickness of from about 10 μm to about500 μm, or about 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm,90 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm,500 μm, or 500 μm, where any value can be a lower and upper endpoint ofa range (e.g., 10 μm to 100 μm).

In one aspect, the unit oral dose compositions optionally include arelease-delaying agent. In another aspect, the unit oral dosecompositions do not include a release-delaying agent. Two common classesof release-delaying agents are “enteric” (i.e., allowing release withina specific milieu of the gastro-intestinal tract) and “fixed-time”(i.e., allowing release after a pre time period after administration,regardless of gastro-intestinal milieu).

Enteric release-delaying agents allow release at a certain pH or in thepresence of degradative enzymes that are characteristically present inspecific locations of the GI tract where release is desired. The entericmaterial typically remains insoluble at gastric pH, then allows forrelease of the active ingredient in the higher pH environment of thedownstream gastrointestinal tract (e.g., often the duodenum, orsometimes the colon). The enteric material includes enzymaticallydegradable polymers that are degraded by bacterial enzymes present inthe lower gastrointestinal tract, particularly in the colon.

Materials used for enteric release formulations include cellulosicpolymers such as hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulosephthalate, methylcellulose, ethyl cellulose, cellulose acetate,cellulose acetate phthalate, cellulose acetate trimellitate andcarboxymethylcellulose sodium; acrylic acid polymers and copolymers,preferably formed from acrylic acid, methacrylic acid, methyl acrylate,ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and othermethacrylic resins that are commercially available under the trademarkEUDRAGIT® (Rohm Pharma; Westerstadt, Germany), including EUDRAGIT®L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® L-100(soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above,as a result of a higher degree of esterification), and EUDRAGIT® NE, RLand RS (water-insoluble polymers having different degrees ofpermeability and expandability); vinyl polymers and copolymers such aspolyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate,vinylacetate crotonic acid copolymer, and ethylene-vinyl acetatecopolymer; enzymatically degradable polymers such as azo polymers,pectin, chitosan, amylose and guar gum; zein and shellac. A preferredcoating agent is methacrylic acid copolymer NF (commonly sold under thetrademark EUDRAGIT® L100-55).

The release-delaying agent allows the release of drug after apredetermined lag period after the composition is brought into contactwith body fluids (“fixed-time delayed release”). Unlike enteric release,fixed-time release is not particularly affected by environmental pH orenzymes.

A large number of fixed-time release-delaying agents are known to thoseof ordinary skill in the art. Exemplary materials which are useful formaking the time-release coating include, by way of example, watersoluble polysaccharide gums such as carrageenan, fucoidan, gum ghatti,tragacanth, arabinogalactan, pectin, and xanthan; water-soluble salts ofpolysaccharide gums such as sodium alginate, sodium tragacanthin, andsodium gum ghattate; water-soluble hydroxyalkylcellulose wherein thealkyl member is straight or branched of 1 to 7 carbons such ashydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylcellulose; synthetic water-soluble cellulose-based laminaformers such as methyl cellulose and its hydroxyalkyl methylcellulosecellulose derivatives such as a member selected from the groupconsisting of hydroxyethyl methylcellulose, hydroxypropylmethylcellulose, and hydroxybutyl methylcellulose; other cellulosepolymers such as sodium carboxymethylcellulose, cellulose acetate,cellulose acetate butyrate and ethyl cellulose; and other materialsknown to those of ordinary skill in the art. Other film-formingmaterials that can be used for this purpose includepoly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend ofgelatin and polyvinyl-pyrrolidone, gelatin, glucose, saccharides,povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate)copolymer. Other materials which can be used in the time-release coatinginclude methacrylic resins commonly sold under the trademarks EUDRAGIT®NE, RL and RS, hydroxypropylcellulose, microcrystalline cellulose (MCC,commonly sold under the trademark AVICEL® from FMC Corp.),poly(ethylene-vinyl acetate) (60:40) copolymer (EVAC from AldrichChemical Co.), 2-hydroxyethylmethacrylate (HEMA), methyl methacrylate(MMA), and calcium pectinate can be included. Substances that are usedas excipients within the pharmaceutical industry can also act asrelease-delaying agents.

Common types of fixed-time release dosage forms include erodibleformulations, formulations that undergo osmotic rupture, or unit dosageform that use any combination of mechanisms for delayed-burst release.

Fixed-time release-delaying agents (RDAs) can optionally achieve adelayed-burst release by osmotic rupture. Examples of such RDAs includeswelling agents, osmogens, binders, lubricants, film formers, poreformers, coating polymers and/or plasticizers.

Osmotic rupture is achieved by a delayed-burst release component, whichincludes a coated unit dosage form that contains the drug and a swellingagent within the semipermeable coating (e.g., ethylcellulose). Thecoating weight (thickness) of the semipermeable coating can be selectedto delay release by osmotic rupture for a desired period. To identifythe correct coating weight for a particular delay, unit dosage formswith a range of coating weights can be tested via in vitro dissolutionto determine the burst time. Based on these results, a coating weightthat achieves the desired lag period would be selected. In addition, theamount and/or ratio of coating strength modifier (e.g., talc) in thecoating can be adjusted as well. Other formulation variables that canalso be adjusted to obtain the desired release by osmotic ruptureinclude the amount of sweller layer and sweller and/or fillers in theformulation. In the case of rupturing tablets, the amount of swellerwould be selected to achieve the target release, while still providingthe tablet with sufficient compressibility and acceptably low friabilityto be manufacturable.

One or more “diffusion regulators” can control the permeation of bodilyfluids and delay the release of a bioactive. Exemplary diffusionregulators include hydrophilic polymers, electrolytes, proteins,peptides, amino acids and others known to those of ordinary skill in thepharmaceutical sciences. In an example, the fixed-time release-delayingagent comprises a coating that permits release of drug after a fixedperiod. The thickness of the coating can affect the time required forpenetration of fluids into the formulation. For example, a diffusioncontrolling time release coating that provides release after a fixeddelay period of about 0.5-2.5 hours could be about 200-1000 micronsthick, and one that provides a release after a fixed delay period ofabout 2.5-5.0 hours could be about 1000-3000 microns thick.

Examples of osmotic rupturing multiparticulates are demonstrated in theliterature (See, e.g., Dashevsky, et al, International Journal ofPharmaceutics, 318, (2006) 124-131; Mohamed, et al, Drug Development andIndustrial Pharmacy, 33 (2007) 113-119; U.S. Pat. No. 4,871,549; Ueda,S., et al, Journal of Drug Targeting, 2 (1994) 35-44; Ueda, S., et al,Chemical Pharmaceutical Bulletin, 42(2), (1994) 359-363; Ueda, S., etal, Chemical Pharmaceutical Bulletin, 42(2), (1994) 364-367). Examplesof osmotic rupturing tablets are demonstrated in the literature (U.S.Pat. No. 4,871,549; Theeuwes, F., Journal of Pharmaceutical Sciences,Vol. 64, No. 12, (1975) 1987-1991; Sungthongjeen, S., et al, Journal ofControlled Release, 95, (2004) 147-159).

Erodible formulations provide another example of fixed-time releaseformulations. The release delay from an erodible coated tablet can beadjusted by those of ordinary skill in the art by regulating theerodible layer coating weight. To identify the correct coating weight,tablets over a range of coating weights can be tested via in vitrodissolution (and/or erosion) to determine the burst time. Otherformulation variables that may affect performance are the selection ofthe coating layer polymer type and viscosity. Examples of erodiblecoated tablets are demonstrated in the literature (Sangalli, M. E., et.al., Journal of Controlled Release, 73 (2001) 103-110; Gazzaniga, A.,et. al., International Journal of Pharmaceutics, 108 (1994) 77-83).

The unit oral dose composition can include one or more “erosionregulators” that control the erosion rate of the coating. Any materialor combination of materials may serve as an erosion regulator. Exemplaryerosion and/or diffusion regulators include hydrophilic polymers,electrolytes, proteins, peptides, amino acids and others known to thoseof ordinary skill in the pharmaceutical sciences. The thickness of thecoating can affect the time required for erosion of the coating. Forexample, an erodible time-release coating that provides release after afixed period of about 0.5-2.5 hours could be about 100-2,000 micronsthick, and one that provides release after a fixed delay period of about2.5-5.0 hours could be about 2,000-5,000 microns thick.

The unit oral dose compositions may include a colorant such as titaniumdioxide, iron oxide-based colorants or others. In one aspect, the outersurface of the unit oral dose composition is coated with colorant havinga blue hue (e.g., dark blue, cobalt blue, exterior blue or blue-purplecolor, purple or violet color, deep blue, sea-blue, denim blue orcolonial blue, or shades of blue, deep blue, blue/purple, sea-purple,violet color, denim blue, colonial blue, brown or tan).

In one embodiment the barrier layer comprises a non-toxic ediblepolymer, edible pigment particles, an edible polymer plasticizer, and asurfactant. Materials include, for example and not limitation, materialsdescribed in U.S. Pat. No. 4,543,370 (Colorcon), incorporated herein byreference. Exemplary barrier layers include that commonly sold under thetrademark OPADRY®, which is available from Colorcon (West Point Pa.USA); that commonly sold under the trademark OPADRY® II which isavailable from Colorcon (West Point Pa. USA) and comprises hydroxypropylmethylcellulose (HPMC), titanium dioxide, plasticizer and othercomponents;

By using sensitive methods to test the dissolution of the oral dosecomposition from solid form into solution at a specified time,percentage differences in the rates of dissolution between differentcompositions can be determined. In one aspect, the unit oral dosecomposition of the present invention is formulated such that, regardlessof the presence or absence of acetaminophen in the unit oral dosecomposition, the dissolution rate of famotidine in the unit oral dosecomposition at a specified time is greater than the dissolution rate ofibuprofen in the unit oral dose composition at the same specified time.In one aspect, the dissolution rate of famotidine is from about 10% toabout 200% greater at a specified time than that of only famotidine atthe same dosage in the unit dose composition over the same specifiedperiod of time during the initial 45 minutes after drug administration(e.g., 0 to 5 minutes, 0 to 10 minutes, 0 to 15 minutes, 0 to 20minutes, 0 to 25 minutes, 0 to 30 minutes, 0 to 45 minutes. In anotheraspect, the dissolution rate of famotidine is from about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about90%, about 100%, about 110%, about 120%, about 130%, about 140%, about150%, about 160%, about 170%, about 180%, about 190%, or about 200% overa specified period of time greater than that of only famotidine at thesame dosage in the unit dose composition over the same specified periodof time (e.g., 0 to 5 minutes, 0 to 10 minutes, 0 to 15 minutes, 0 to 20minutes, 0 to 30 minutes, 0 to 45 minutes, etc.), where any value can bea lower and upper endpoint of a range (e.g., about 50% to about 150%).

In one aspect, the dissolution rate of famotidine is from about 10% toabout 200% greater over a specified period of time than the dissolutionrate of ibuprofen in the unit dose composition over the same specifiedperiod of time during the initial 45 minutes after drug administration(e.g., 0 to 5 minutes, 0 to 10 minutes, 0 to 15 minutes, 0 to 20minutes, 0 to 25 minutes, 0 to 30 minutes, 0 to 45 minutes). In anotheraspect, the dissolution rate of famotidine is from about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about90%, about 100%, about 110%, about 120%, about 130%, about 140%, about150%, about 160%, about 170%, about 180%, about 190%, or about 200% overa specified period of time greater than that of ibuprofen in the unitdose composition over the same specified period of time (e.g., 0 to 5minutes, 0 to 10 minutes, 0 to 15 minutes, 0 to 20 minutes, 0 to 30minutes, 0 to 45 minutes), where any value can be a lower and upperendpoint of a range (e.g., about 50% to about 150%).

In one aspect, the dissolution rate of famotidine in the unit oral dosecomposition in said human is measured over a specified time period(e.g., within the initial 15 to 45 minutes). In another aspect, thedissolution rate of famotidine in the unit oral dose composition in saidhuman measured at a specified time (for example, at about 5 minutes orat about 10 minutes) is greater than the dissolution rate of ibuprofenin the unit oral dose composition in said human because ibuprofen isnon-detectable or very low at the same specified time.

In one aspect, the famotidine in the unit oral dose composition has adissolution rate that is about 10% to about 30% greater than thedissolution rate of ibuprofen at about 5 minutes, at about 10 minutes,at about 15 minutes, at about 20 minutes, at about 25 minutes, at about30 minutes or at about 45 minutes after administration of the unit oraldose composition to the human. In another aspect, for example, about 50%of the famotidine is released from the unit oral dose composition about15 minutes after administration of said unit oral dose composition insaid human and about 25% of the ibuprofen is released from the unit oraldose composition about 15 minutes after administration of said unit oraldose composition in said human, indicating that about 25% morefamotidine (i.e., 50%-25%) is dissolved in said human than ibuprofen at15 minutes in said human. Since 50% dissolution is 2 times the 25%absolute difference in dissolution rates, the dissolution of famotidineis 2 times greater than the dissolution of ibuprofen at 15 minutes. Inanother aspect, about 80% of the famotidine is released from the unitoral dose composition about 30 minutes after administration of said unitoral dose composition in said human and about 40% of the ibuprofen isreleased from the unit oral dose composition about 30 minutes afteradministration of said unit oral dose composition in said human,indicating that about 40% famotidine (i.e., 80%-40%) is dissolved insaid human than ibuprofen at 30 minutes in said human. Since 80%dissolution is 2 times the 40% absolute difference in dissolution rates,the dissolution of famotidine is 2 times greater than the dissolution ofibuprofen at 30 minutes.

In one aspect, the famotidine in the unit oral dose composition has adissolution rate at about 10 minutes after administration of said unitoral dose composition to said human that is about 5 minutes to less than10 minutes earlier than the time required for ibuprofen in said unitoral dose composition to achieve the same dissolution rate afteradministration of the unit oral dose composition to the human. Forexample, if 50% of the famotidine is released from the unit oral dosecomposition 10 minutes after administration of said unit oral dosecomposition, and 50% of the ibuprofen is released from the unit oraldose composition at about 20 minutes after administration of said unitoral dose composition, then famotidine is released about 10 minutesearlier than ibuprofen (i.e., famotidine is dissolved earlier thanibuprofen from the unit oral dose composition).

In one aspect, the famotidine in the unit oral dose composition has adissolution rate at about 15 minutes after administration of said unitoral dose composition to said human that is about 5 minutes to about 10minutes earlier than the time required for ibuprofen in said unit oraldose composition to achieve the same dissolution rate afteradministration of the unit oral dose composition to the human (i.e.,famotidine is dissolved earlier than ibuprofen).

In another aspect, the famotidine in the unit oral dose composition hasa dissolution rate at about 20 minutes after administration of said unitoral dose composition to said human that is about 5 minutes to about 15minutes earlier than the time required for ibuprofen in said unit oraldose composition to achieve the same dissolution rate afteradministration of the unit oral dose composition to the human (i.e.,famotidine is dissolved earlier than ibuprofen).

In another aspect, the famotidine in the unit oral dose composition hasa dissolution rate at about 30 minutes after administration of said unitoral dose composition to said human that is about 5 minutes to about 25minutes earlier than the time required for ibuprofen in said unit oraldose composition to achieve the same dissolution rate afteradministration of the unit oral dose composition to the human (i.e.,famotidine is dissolved earlier than ibuprofen).

In another aspect, the famotidine in the unit oral dose composition hasa dissolution rate at about 45 minutes after administration of said unitoral dose composition to said human that is about 5 minutes to about 40minutes earlier than the time required for ibuprofen in said unit oraldose composition to achieve the same dissolution rate afteradministration of the unit oral dose composition to the human (i.e.,famotidine is dissolved earlier than ibuprofen).

The dissolution rate can be determined using in vitro techniques knownin the art. The specific dissolution technique employed is determined bythe dosage form characteristics and the intended route ofadministration. For solid dosage forms, industry standard dissolutiontesting methodologies include the United States Pharmacopoeia (USP)Apparatus 1 (basket) and the USP Apparatus 2 (paddle).Immediate-release, modified-release and extended release tablets areusually tested in classical dissolution baths with USP 2 paddles.Floating capsules and tablets generally use USP 1 baskets. Otherdissolution techniques and equipment include USP 3 (reciprocatingcylinders), USP 4 (flow-through-cell), USP 5 (paddle-over-disk), USP 6(cylinder) and USP 7 (reciprocating holders). The development of adissolution procedure involves selecting the dissolution media,apparatus type and hydrodynamics (agitation rate) appropriate for theproduct.

In one aspect, an in vitro dissolution assay is carried out by placingthe unit oral dose composition in a known volume of dissolution mediumin a container with a suitable stirring device (e.g., a rotating basketor paddle of specified size and shape). Samples of the medium arewithdrawn at various times over 60 minutes and analyzed for dissolvedactive substance to determine the rate of dissolution. In one aspect,the dissolution method increases the number of units tested per assay(up to 48 tablets) and samples are obtained at more frequent intervals(at 5-minute intervals over 60 minutes) to improve the sensitivity andaccuracy of the dissolution assay. Dissolution may be measured asdescribed for ibuprofen in the USP or, alternatively, as described forfamotidine in the USP. For example, the unit dose composition is placedin a vessel of a United States Pharmacopeia dissolution apparatus II(Paddles) containing 900 ml dissolution medium at 37° C. The paddlespeed is 50 RPM. Independent measurements are made for at least three(3) unit dose compositions. In one suitable in vitro assay, dissolutionis measured using a neutral dissolution medium such as 50 mM potassiumphosphate buffer, pH 7.2 (“neutral conditions”). In another aspect, thedissolution rate is measured in a Type II dissolution apparatus(paddles) according to U.S. Pharmacopoeia 29 at 37° C. in 50 mMpotassium phosphate buffer, pH 7.2 at 50 rotations per minute.

Described herein are unit oral dose compositions for reducing theoccurrence of heartburn and/or reducing the severity of heartburn in ahuman when taking ibuprofen for the treatment of acute pain. The unitoral dose compositions described herein are particularly useful tohumans with a history indicating they experience heartburn when takingover-the-counter (OTC) NSAIDs such as ibuprofen, naproxen sodium, andaspirin (acetylsalicylic acid) for acute pain relief. In one aspect, theunit dose compositions reduce the occurrence and/or severity ofheartburn in a human that takes OTC ibuprofen for the treatment of acutepain. In another aspect, the unit dose compositions reduce the severityof heartburn in a human that takes OTC ibuprofen for the treatment ofacute pain.

Heartburn can be measured on different heartburn rating scales. Theabsence or presence of heartburn at a specified time can be measured ona nominal scale (“I have no heartburn” or “I have heartburn”). On ratinginstruments that measure the intensity of heartburn, the absence ofheartburn can be measured as “no heartburn” on a categorical heartburnintensity scale; as 0 (zero) on a 0-to-10 numerical heartburn ratingscale; or as 0 (zero) on a 0-to-100 mm linear, or visual analog,heartburn intensity rating scale. Consequently, the percentage ofsubjects who report “no heartburn” over the treatment period of aclinical study can be determined (e.g., 35% of the subjects using theunit oral dose composition had no heartburn, compared to 85% of thesubjects using ibuprofen, indicating a significant 50% difference, orreduction, in the occurrence of heartburn). Similarly, the percentage ofsubjects who report the occurrence of any heartburn over the treatmentperiod of a clinical study can also be determined. Thus, for example, if65% of the subjects using ibuprofen had heartburn, compared to 15% ofthe subjects using the unit oral dose composition, these resultsidentify 50% absolute difference in the occurrence of heartburn. Inother words, there is about 77% relative risk reduction for a humanusing the unit oral dose composition compared to a human using the samedosage strength of ibuprofen. In another aspect, when the clinical studyincludes subjects taking a placebo resulting in 16% with heartburn(i.e., comparable to 15% of the subjects using the unit oral dosecomposition), these results indicate that the unit oral dose compositionprevents ibuprofen-induced heartburn.

In another aspect, described herein are unit oral dose compositions forreducing the risk of occurrence and/or severity of heartburn in a humanwhen taking ibuprofen. In this aspect, the unit oral dose compositionsprevent heartburn altogether when compared to the oral administration tothe human of the same dosage strength of said ibuprofen. In one aspect,the unit oral dose compositions reduce the risk of occurrence and/orseverity of heartburn in a human when taking ibuprofen by at least 10%,at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 95%, or up to 100% whencompared to the oral administration to the human of the same dosagestrength of said ibuprofen in the absence of said famotidine.

Heartburn intensity scales also provide measurements of the severity (orintensity) of heartburn: by categories of heartburn intensity on acategorical heartburn intensity scale (“mild heartburn,” “moderateheartburn,” “severe heartburn”); by the numbers 1 through 10 on anumerical heartburn rating scale, where, for example, “1-3” representsmild heartburn, “4-6” represents moderate heartburn, and “7-10”represents “severe heartburn;” or on a linear, or visual analog, scalewith ratings from 1 mm to 100 mm, which represents “severe heartburn.” Asubject's total experience with heartburn can be expressed as the sum ofheartburn intensity ratings over a specified period of time, showing howmuch heartburn subjects experience as a result of using differentcompositions. In one aspect, summed heartburn severity can be measuredover a specified period of time (e.g., over 1 hour, over 2 hours, over 4hours, over 6 hours, over 8 hours, over 10 hours, over 12 hours, over 24hours, over 48 hours) after only the initial dose and comparisons can bemade between treatments. In another aspect, summed heartburn severitycan be measured over a specified time period (e.g., over 2 hours, over 4hours, over 6 hours, over 8 hours, over 10 hours, over 12 hours, over 24hours, over 48 hours) after multiple doses and comparisons can be madebetween treatments (e.g., subjects using only ibuprofen reported moresevere heartburn than subjects using the unit oral dose composition).

In another aspect, the unit oral dose compositions reduce the severityof heartburn in a human by at least 10%, at least 20%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 95%, or up to 100% when compared to the oraladministration to the human of the same dosage strength of saidibuprofen over a specified period of time (e.g., over 1 hour, over 2hours, over 4 hours, over 6 hours, over 8 hours, over 10 hours, over 12hours, over 24 hours, over 48 hours).

In one aspect humans administered the unit oral dose compositionsdescribed herein report lower levels of heartburn severity over aspecified period of time (e.g., over 1 hour, over 2 hours, over 4 hours,over 6 hours, over 8 hours, over 10 hours, over 12 hours, over 24 hours)after administration of a single unit oral dose composition than humansadministered famotidine to treat ibuprofen-induced heartburn that occursafter the administration of a single oral unit of ibuprofen. In anotheraspect, summed heartburn severity over a specified period of time (e.g.,over 1 hour, over 2 hours, over 4 hours, over 6 hours, over 8 hours,over 10 hours, over 12 hours, over 24 hours) is reduced by at least 10%,at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 95%, or up to 100% forhumans administered a single unit oral dose composition described hereinwhen compared to the single oral administration to the human of the samedosage strength of said ibuprofen over the same specified period of timefollowed by the administration of famotidine to treat ibuprofen-inducedheartburn. In another aspect, summed heartburn severity for humansadministered one, two, or three doses of the unit oral dose compositionsdescribed herein over a specified period of time (e.g., over 1 hour,over 2 hours, over 4 hours, over 6 hours, over 8 hours, over 10 hours,over 12 hours, over 24 hours) is reduced by at least 10%, at least 20%,at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80%, at least 90%, at least 95%, or up to 100% when compared tothe oral administration to the human of the same dosage strength of saidibuprofen at the same treatment regimen followed by the administrationof famotidine to treat ibuprofen-induced heartburn over the samespecified period of time. These outcomes indicate that theco-administration of famotidine with ibuprofen in the unit oral dosecompositions reduces the severity of heartburn more than treatingibuprofen-induced heartburn by administering famotidine after heartburnoccurs.

The unit dose compositions described herein provide a reduction in theseverity of heartburn pain and the prevention of heartburn pain in ahuman when compared to the oral administration to the same human of thesame dosage strength of famotidine for the treatment of heartburn. Notwishing to be bound by theory, by blocking the receptor on gastricparietal cells that produce gastric acid and cause heartburn in thestomach and esophagus, famotidine also reduces the amount of gastricfluid produced by gastric parietal cells that can be refluxed into theesophagus. With less volume of gastric fluid, the stomach also emptiesfaster, which can promote increased earlier absorption of ibuprofen fromthe intestine. As a result, with reduced severity or non-occurrence ofheartburn caused by the anti-secretory activity of famotidine, the humanwould experience enhanced analgesic activity (i.e., reduction of pain)from ibuprofen due to increased early absorption of ibuprofen. Uponadministration of the unit oral dose composition the human would alsoexperience a greater reduction in the severity of heartburn pain orprevention of heartburn pain.

Not wishing to be bound by theory, the concomitant sensation ofheartburn lowers the threshold at which a human experiences acute pain.A human with heartburn is more sensitive to pain (i.e., has a lower painthreshold) and typically reports greater acute pain than when the humanhas no or minimal heartburn. As a result, the human with acute pain isless responsive to the anti-nociceptive activity of an administeredanalgesic such as ibuprofen. Because the human with heartburn is moresensitive to acute pain and reports greater pain severity, the samehuman experiences less reduction in pain severity and less pain relieffrom the same dosage strength of an analgesic than when there is less orno heartburn. In contrast, when the human's pain threshold is notaffected by heartburn (e.g., when treated with famotidine present in theunit oral dose ibuprofen-famotidine compositions described herein), thesubject experiences greater reduction in pain severity and more painrelief. Therefore, for subjects with acute pain who report heartburninduced by OTC NSAIDs like ibuprofen, naproxen sodium, and aspirin, theunit oral dose compositions described herein can result in greateranalgesic activity when compared to only the use of ibuprofen. As aresult of reducing the severity and/or occurrence of heartburn inducedby taking ibuprofen, the unit oral dose compositions described hereinprovide enhanced pain reduction for the subject with ibuprofen-inducedheartburn when compared to when the subject with ibuprofen-inducedheartburn uses only orally administered ibuprofen. As discussed above,the pain threshold is lowered for subjects with heartburn induced bytaking ibuprofen but restored by the administration of fast-dissolvingfamotidine, thus enhancing pain relief by the co-administered ibuprofenin the unit oral dose composition. Also as discussed above, famotidinereduces the amount of gastric fluid produced by parietal cells, whichmeans the stomach contains less gastric fluid. Here the stomach emptiesfaster, which promotes earlier absorption of ibuprofen from theintestine. By reducing the production of gastric fluid, famotidinefurther enhances greater and faster pain relief due to ibuprofen.Moreover, as a result of an enhanced absorption of ibuprofen, lessibuprofen (i.e., smaller doses and/or fewer doses of ibuprofen over 24hours) may be required to produce equal pain relief (“equi-analgesia”)compared to standard dosages of ibuprofen (e.g., 200 mg, 250 mg, 400 mg)or to total daily dosages of ibuprofen (e.g., 200 mg, 400 mg, 600 mg,750 mg, 800 mg, 1,000 mg, or 1,200 mg). The unit oral dose compositionsdescribed herein thus provide enhanced pain reduction for the subjectwith ibuprofen-induced heartburn when compared to when the subject usesonly orally administered ibuprofen.

The unit oral dose compositions described herein effect the severity ofacute pain. The sensation of pain can be measured utilizing differentpain intensity rating scales. The absence or presence of pain, forexample, can be measured on a nominal scale (“I have no pain” or “I havepain”). On rating instruments that measure the intensity of pain, theabsence of pain is measured as “no pain” on a categorical pain intensityscale; as 0 on a 0-to-10 numerical rating scale; and as 0 on a 100-mmlinear, or visual analog, scale. As measured on these pain intensityscales one can determine the percentage of subjects in a treatment groupwho report “no pain” at a specified time to identify differences inanalgesic efficacy between treatments, showing, for example, that moresubjects using the unit oral dose composition reported no pain thansubjects using ibuprofen over a specified period of time and how quicklysubjects achieve this endpoint.

Similarly, one can determine the percentage of subjects in a treatmentgroup who require an additional analgesic over a specified period oftime to identify differences in analgesic efficacy between treatments,showing, for example, that more subjects using ibuprofen required anadditional analgesic than subjects using the unit oral dose compositionover a specified period of time.

Changes in pain over time can also be measured on pain intensity scales,which include: categories (mild, moderate, severe on a categoricalscale; the numbers 1 through 10 in a numerical rating scale, where, forexample, “1-3” represents mild pain, “4-6” represents moderate pain, and“7-10” represents “severe pain;” or ratings from 1 mm to 100 mm on avisual analog scale. Changes measured on these pain intensity scales canbe expressed as pain intensity difference (PID) or as per centagedifference in pain intensity (% PID) at a specified time. The effects onpain intensity can be expressed as the percentage of subjects with atleast 50% reduction of pain (or “pain half-gone”) over a specifiedperiod of time to identify differences in analgesic efficacy betweentreatments, showing, for example, that more subjects using the unit oraldose composition reported at least 50% pain reduction than subjectsusing ibuprofen over a specified period of time and how quickly subjectsachieve this endpoint.

In another aspect, the unit oral dose compositions reduce the severityof pain in a human by at least 10%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 95%, or up to 100% when compared to the oraladministration to the human of the same dosage strength of saidibuprofen over a specified period of time (e.g., over 1 hour, over 2hours, over 4 hours, over 6 hours, over 8 hours, over 10 hours, over 12hours, over 24 hours, over 48 hours).

In another aspect, differences in pain intensity are added as summedpain intensity differences (SPID) or as summed per centage painintensity differences (% SPID) over a specified period of time (e.g.,SPID4, indicating SPID over 4 hours, or % SPID4, indicating % SPID over4 hours, or SPID24, indicating SPID over 24 hours, or % SPID24,indicating % SPID over 24 hours; or SPID48, indicating SPID over 48hours, or % SPID48, indicating % SPID over 48 hours; etc.), representingthe total pain reduction which a subject experiences. SPID and % SPIDcan thus be compared between treatments to identify differences inoverall analgesia attributable to specific compositions, for example,showing that subjects using the unit oral dose composition reported morepain reduction than subjects using ibuprofen.

The effect of the unit oral dose compositions described herein inrelieving acute pain can also be measured directly on pain reliefscales. These measure increasing degrees of relief: for example, on acategorical relief scale as the categories of “mild relief,” “moderaterelief,” or “complete relief;” on a 0-to-10 numerical relief scale,where the number 10 represents “complete relief” and 1 to 9 represent anincreasing extent of relief; or, on a visual analog scale, where a100-mm rating represents “complete relief,” with 1 to 99 mm ratingsrepresenting an increasing extent of relief. In one aspect, thepercentage of subjects in a treatment group who report “moderate relief”on a categorical scale can be determined, with comparisons on thismetric indicating analgesic differences attributable to each composition(e.g., more subjects using the unit oral dose composition reportedmoderate relief by 90 minutes than subjects using ibuprofen). In anotheraspect, one can determine the per centage of subjects who report“complete relief” over a specified period of time to identifydifferences in analgesic efficacy between treatments, showing, forexample, that more subjects using the unit oral dose compositionreported complete relief than subjects using ibuprofen over a specifiedperiod of time and how quickly subjects achieve the endpoint of completerelief.

In another aspect total pain relief ratings are summed to produce totalpain relief (TOTPAR) scores over a specified period of time (e.g.,TOTPAR4, indicating the total pain relief which a subject experiencedover 4 hours). TOTPAR scores are compared between treatment groups toidentify differences in analgesic efficacy, showing, for example, thatsubjects using the unit oral dose composition reported more relief ofpain than subjects using ibuprofen over a specified period of time.

In another aspect, differences in the onset of analgesic activity afteronly the initial dose of the unit oral dose composition can be comparedwith only the initial dose of on measurements, for example, of painintensity, pain relief, total pain relief, summed pain intensitydifference, summed percentage pain intensity difference during the firsthour after administration (e.g., the initial 15 minutes, the initial 30minutes, the initial 45 minutes, the initial 60 minutes) or over aspecified period of time (e.g., the first 2 hours, the first 4 hours,the first 6 hours, the first 8 hours); on measurements of the time topeak pain relief, the time to peak pain intensity difference, the timeto peak % pain intensity difference; or on measurements of thepercentage of subjects with at least moderate relief or with greaterthan moderate relief over the first hour (over the first 2 hours, overthe first 4 hours, over the first 6 hours, over the first 8 hours),indicating an earlier onset of action of the unit oral dose compositionthan ibuprofen.

In another aspect the duration of pain reduction (i.e., PID or % PID,SPID or % SPID) can be examined at specified time points (e.g., at 6hours, at 8 hours, at 10 hours, at 12 hours, at 16 hours, at 20 hours,at 24 hours) after only the initial dose, indicating a longer durationof action of the unit oral dose composition than the initial dose ofonly ibuprofen. In another aspect the duration of pain relief can beexamined at later specified time points (e.g., at 30 hours, at 36 hours,at 48 hours, at 72 hours), indicating, for example, that significantlymore subjects using the unit oral dose composition still reported atleast moderate relief of pain or that subjects using the unit oral dosecomposition reported greater pain reduction over 48 hours or 72 hours,for example, than subjects using the same number of doses of ibuprofenat the same treatment regimen).

The unit oral dose compositions described herein provide enhanced painreduction (measured by pain intensity) and/or greater pain relief(measured directly) when compared to orally administered ibuprofen whichis followed by famotidine administered orally to relieve the heartburninduced by ibuprofen. Ibuprofen taken in the unit oral dose compositioncontaining famotidine provides greater pain reduction and/or greaterpain relief to the human than ibuprofen followed by administeringfamotidine to treat ibuprofen-induced heartburn.

In one aspect humans administered the unit oral dose compositionsdescribed herein report lower levels of pain intensity frompre-treatment pain intensity, resulting in greater pain reduction over aspecified period of time (e.g., over 1 hour, over 2 hours, over 4 hours,over 6 hours, over 8 hours, over 10 hours, over 12 hours, over 24 hours,over 48 hours) after administration of a single unit oral dosecomposition than humans administered famotidine to treatibuprofen-induced heartburn after it occurs. In one aspect humansadministered the unit oral dose compositions described herein reportlower levels of pain intensity from pre-treatment pain intensity atspecific time points after administration of the unit dose composition(e.g., at about 15 minutes, at about 20 minutes, at about 30 minutes, atabout 45 minutes, at about 60 minutes, at about 2 hours, at about 4hours, at about 6 hours, at about 8 hours, at about 10 hours, at about12 hours, at about 24 hours), resulting in greater percentage painreduction (% pain intensity difference, or % PID) than humansadministering famotidine to treat ibuprofen-induced heartburn after itoccurs.

In another aspect, humans administered the unit oral dose compositionsdescribed herein report lower levels of pain intensity frompre-treatment pain intensity, resulting in greater overall painreduction (i.e., summed pain intensity difference, or SPID) over aspecified period of time (e.g., SPID over 30 minutes, over 1 hour, over2 hours, over 4 hours, over 6 hours, over 8 hours, over 10 hours, over12 hour, over 24 hours) after the initial dose than humans administeringfamotidine to treat ibuprofen-induced heartburn after it occurs.

In another aspect, humans administered the unit oral dose compositionsdescribed herein report lower levels of pain intensity frompre-treatment pain intensity after the initial dose, resulting ingreater overall percentage pain reduction (% summed pain intensitydifference, or % SPID) over a specified period of time than humansadministering famotidine to treat ibuprofen-induced heartburn after itoccurs (e.g., over 1 hour (% SPID1), over 2 hours (% SPID2), over 4hours (% SPID4), over 6 hours (% SPID6), over 8 hours (% SPID8), over 12hours (% SPID12), over 24 hours (% SPID24).

In one aspect, SPID1 for the unit dose composition described herein isgreater than SPID1 for ibuprofen. In another aspect, SPID2 for the unitdose composition described herein is greater than SPID2 for ibuprofen,SPID4 for the unit dose composition described herein is greater thanSPID4 for ibuprofen, SPID6 for the unit dose composition describedherein is greater than SPID6 for ibuprofen, SPID8 for the unit dosecomposition described herein is greater than SPID8 for ibuprofen, SPID12for the unit dose composition described herein is greater than SPID12for ibuprofen.

In another aspect, a single unit oral dose composition described hereinprovides % SPID4 that is greater than or the same as the % SPID4 for twodoses of ibuprofen. In another aspect, a single unit oral dosecomposition described herein provides % SPID8 that is greater than orthe same as the % SPID8 for two doses of ibuprofen. In another aspect, asingle unit oral dose composition described herein provides % SPID10that is greater than or the same as the % SPID10 for two doses ofibuprofen. In another aspect, a single unit oral dose compositiondescribed herein provides % SPID12 that is greater than or the same asthe % SPID12 for two doses of ibuprofen.

In another aspect, humans administered a single unit oral dosecomposition described herein report greater levels of pain relief atspecified time points (e.g., at about 15 minutes, at about 20 minutes,at about 30 minutes, at about 45 minutes, at about 60 minutes, at about2 hours, at about 4 hours, at about 6 hours, at about 8 hours, at about10 hours, at about 12 hours, at about 24 hours) after the initial dosewhen compared to humans administered famotidine to treat heartburnfollowing one unit oral dose of ibuprofen. In another aspect, humansadministered a single unit oral dose composition described herein afterthe initial dose report greater levels of total pain relief (TOTPAR)over a specified period of time (e.g., over 2 hours (TOTPAR2), over 4hours (TOTPAR4), over 6 hours (TOTPAR6), over 8 hours (TOTPAR8), over 12hours (TOTPAR12), over 24 hours (TOTPAR24), etc.) than humansadministering famotidine to treat heartburn following one unit oral doseof ibuprofen.

In another aspect a greater percentage of humans administered the unitoral dose compositions described herein report at least moderate reliefof pain over a specified period of time after the initial dose (e.g.,over 30 minutes, over 1 hour, over 2 hours, over 4 hours, over 6 hours,over 8 hours, over 10 hours, over 12 hours, over 24 hours, over 48hours) than humans administering famotidine to treat ibuprofen-inducedheartburn after it occurs. In another aspect a greater percentage ofhumans administered the unit oral dose compositions described hereinreport greater than moderate relief of pain over a specified period oftime (e.g., over 30 minutes, over 1 hour, over 2 hours, over 4 hours,over 6 hours, over 8 hours, over 10 hours, over 12 hours, over 24 hours,over 48 hours) after the initial dose than humans administeringfamotidine to treat ibuprofen-induced heartburn after it occurs.

In another aspect, pain reduction is increased by at least about 20%over the initial hour following the administration of the unit oral dosecomposition compared to a human who is only administered ibuprofen atthe same treatment regimen. In another aspect, pain reduction isincreased by at least about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90, about 95%, or about 100% overthe initial hour following the administration of the unit oral dosecomposition compared to a human only administered ibuprofen. In oneaspect, the human is administered one solid dosage form of the unit oraldose composition over 1 hour. In another aspect, the human isadministered two solid dosage forms of the unit oral dose compositionover 1 hour.

In another aspect, pain reduction is increased by at least about 20%over the initial 2 hours following the administration of the unit oraldose composition compared to a human who is administered only ibuprofenat the same treatment regimen. In another aspect, pain reduction isincreased by at least about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90, about 95%, or about 100% overthe initial 2 hours following the administration of the unit oral dosecomposition compared to a human only administered ibuprofen. In oneaspect, the human is administered one solid dosage form of the unit oraldose composition over 2 hours. In another aspect, the human isadministered two solid dosage forms of the unit oral dose compositionover 2 hours.

In another aspect, pain reduction is increased by at least about 20%over the initial 4 hours following the administration of the unit oraldose composition compared to a human who is administered only ibuprofenat the same treatment regimen. In another aspect, pain reduction isincreased by at least about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90, about 95%, or about 100% over theinitial 4 hours following the administration of the unit oral dosecomposition compared to a human only administered ibuprofen. In oneaspect, the human is administered one solid dosage form of the unit oraldose composition over 4 hours. In another aspect, the human isadministered two solid dosage forms of the unit oral dose composition atthe same treatment regimen over 4 hours.

In another aspect, pain reduction is increased by at least about 20%over the initial 6 hours following the administration of the unit oraldose composition compared to a human who is administered only ibuprofenat the same treatment regimen. In another aspect, pain reduction isincreased by at least about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90, about 95%, or about 100% over theinitial 6 hours following the administration of the unit oral dosecomposition compared to a human only administered ibuprofen. In oneaspect, the human is administered one solid dosage form of the unit oraldose compositions over 6 hours. In another aspect, the human isadministered two solid dosage forms of the unit oral dose compositionsat the same treatment regimen over 6 hours.

In another aspect, pain reduction is increased by at least about 20%over the initial 8 hours following the administration of the unit oraldose composition compared to a human who is administered only ibuprofenat the same treatment regimen. In another aspect, pain reduction isincreased by at least about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90, about 95%, or about 100% over theinitial 8 hours following the administration of the unit oral dosecomposition compared to a human only administered ibuprofen. In oneaspect, the human is administered one solid dosage form of the unit oraldose composition over 8 hours. In another aspect, the human isadministered two solid dosage forms of the unit oral dose composition atthe same treatment regimen over 8 hours.

In another aspect, pain reduction is increased by at least about 20%over the initial 12 hours following the administration of the unit oraldose composition compared to a human who is administered only ibuprofenat the same treatment regimen. In another aspect, pain reduction isincreased by at least about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90, about 95%, or about 100% over theinitial 12 hours following the administration of the unit oral dosecomposition compared to a human only administered ibuprofen. In oneaspect, the human is administered one solid dosage form of the unit oraldose composition over 12 hours. In another aspect, the human isadministered two solid dosage forms of the unit oral dose composition atthe same treatment regimen over 12 hours.

In one aspect, pain reduction is increased by at least about 20% overthe initial 24 hours following the administration of the unit oral dosecomposition (e.g., two solid dosage forms such as tablets or capsules)compared to a human who is administered only ibuprofen at the sametreatment regimen. In another aspect, pain reduction is increased by atleast about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90, about 95%, or about 100% over the initial 24 hoursfollowing the administration of the unit oral dose composition comparedto a human only administered ibuprofen.

In one aspect, pain reduction is increased by at least about 20% overthe initial 24 hours following the administration of two solid dosageforms (e.g., tablets or capsules) of the unit oral dose compositioncompared to a human who is administered two solid dosage forms of onlyibuprofen at the same treatment regimen. In another aspect, painreduction is increased by at least about 25%, about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90, about 95%, or about 100%over the initial 24 hours following the administration of the unit oraldose composition compared to a human only administered ibuprofen at thesame treatment regimen. In one aspect, the human is administered three,four, five or six solid dosage forms of the unit oral dose compositionsover 24 hours compared to a human who is administered ibuprofen at thesame treatment regimen.

In one aspect, the unit oral dose composition provides enhanced painreduction in said human who develops ibuprofen-induced-heartburn whencompared to the administration to said human of the same dosage strengthof only ibuprofen (i.e., in the absence of said famotidine). In anotheraspect, pain reduction is increased by at least about 20% over theinitial 24 hours following the administration of the unit oral dosecomposition compared to said human who develops ibuprofen-inducedheartburn when administered the same dosage strength of only ibuprofenat the same treatment regimen. In another aspect, pain reduction isincreased by at least about 30% over the initial 24 hours following theadministration of the unit oral dose composition compared to said humanwho develops ibuprofen-induced heartburn over the same treatment regimenwhen administered the same dosage strength of only ibuprofen. In anotheraspect, pain reduction is increased by at least about 40% over theinitial 24 hours following the administration of the unit oral dosecomposition compared to said human who develops ibuprofen-inducedheartburn over the same treatment regimen when administered the samedosage strength of only ibuprofen. In another aspect, pain reduction isincreased by at least about 50% over the initial 24 hours following theadministration of the unit oral dose composition compared to said humanwho develops ibuprofen-induced heartburn over the same treatment regimenwhen administered the same dosage strength of only ibuprofen.

In another aspect, pain reduction is increased by at least about 20%over the initial 4 hours following the administration of the unit oraldose composition compared to said human who develops ibuprofen-inducedheartburn over the same treatment regimen when administered the samedosage strength of only ibuprofen. In another aspect, pain reduction isincreased by at least about 30% over the initial 8 hours following theadministration of the unit oral dose composition compared to said humanwho develops ibuprofen-induced heartburn over the same treatment regimenwhen administered the same dosage strength of only ibuprofen. In anotheraspect, pain reduction is increased by at least about 40% over theinitial 8 hours following the administration of the unit oral dosecomposition compared to said human who develops ibuprofen-inducedheartburn over the same treatment regimen when administered the samedosage strength of only ibuprofen. In another aspect, pain reduction isincreased by at least about 50% over the initial 4 hours following theadministration of the unit oral dose composition compared to said humanwho develops ibuprofen-induced heartburn over the same treatment regimenwhen administered the same dosage strength of only ibuprofen.

In one aspect, the unit oral dose composition provides enhanced painreduction in said human when compared to the oral administration to saidhuman of twice the dosage strength of orally administered ibuprofen inthe absence of said famotidine at the initial dose. In one aspect, theinitial unit oral dose composition administered to the human is only onetablet or capsule, and the initial unit oral dose of ibuprofen alone istwo tablets or capsules, with comparisons of analgesic outcomes, asidentified above, between the two different dosage strengths. In oneaspect, for example, the initial unit oral composition contains 200 mgof ibuprofen, and the initial unit oral dose of ibuprofen alone is 400mg of ibuprofen (signifying 50% less ibuprofen per dose). In anotheraspect, the initial unit oral composition contains 150 mg of ibuprofen,and the initial unit oral dose of ibuprofen alone is 200 mg of ibuprofen(signifying 25% less ibuprofen per dose). Similar paradigms can beapplied to other dosages of the unit dose composition that are lowerthan customary dosages of ibuprofen. In other words, reduced amounts ofibuprofen in single and multiple doses may be required to achieve atleast the same level of pain reduction when using the unit oral dosecompositions described herein.

Depending upon the dosage strengths of ibuprofen and famotidine in theunit oral dose composition, the number of unit oral dose compositionsthat can be administered to the human can vary over a 24-hour period.The unit oral dose compositions can be administered to the human as asingle administration or multiple administrations as needed in a 24-hourperiod. In one aspect, unit oral dose compositions containing onlyibuprofen 200 mg can be administered about every 4 to 6 hours as neededfor a total of six units in a 24-hour period (i.e., a total of 1200 mgof ibuprofen in a 24-hour period). In one aspect, the unit oral dosecomposition containing 200 mg of ibuprofen with famotidine can beadministered followed by a second unit oral dose composition, followedby a third and fourth unit oral dose composition 4 to 6 hours later,followed by fifth and sixth unit oral dose compositions 4 to 6 hourslater for a total of six units in a 24-hour period (i.e., a total of1200 mg of ibuprofen in a 24-hour period). In another aspect, two unitoral dose compositions each containing ibuprofen 200 mg with famotidinecan be administered together followed by third and fourth unit oral dosecomposition 4 to 6 hours later, followed by fifth and sixth unit oraldose compositions 4 to 6 hours later for a total of six units in a24-hour period (i.e., a total of 1200 mg of ibuprofen in a 24-hourperiod). In another aspect, two unit oral dose compositions eachcontaining ibuprofen 200 mg with famotidine can be administered togetherfollowed by third and fourth unit oral dose composition 4 to 12 hourslater for a total of four units in a 24-hour period (thus reducing thetotal daily dosage of ibuprofen to 800 mg). In another aspect, one unitoral dose composition containing ibuprofen 200 mg with famotidine can beadministered, followed by a second unit oral dose composition 4 to 6hours later, followed by a third unit oral dose composition 4 to 6 hourslater, for a total of three units in a 24-hour period (thus reducing thetotal daily dosage of ibuprofen to 600 mg). In another aspect, one unitoral dose composition containing ibuprofen 250 mg with famotidine can beadministered, followed by a second unit oral dose composition about 8hours later, followed by a third unit oral dose composition about 8hours later, for a total of three units in a 24-hour period (thusreducing the total daily dosage of ibuprofen to 750 mg). In anotheraspect, one unit oral dose composition containing ibuprofen 400 mg withfamotidine can be administered, followed by a second unit oral dosecomposition 4 to 12 hours later for a total of two units in a 24-hourperiod (i.e., a total of 800 mg of ibuprofen in a 24-hour period). Inanother aspect, two unit oral dose compositions each containingibuprofen 150 mg with famotidine can be administered together followedby third and fourth unit oral dose composition 4 to 12 hours later for atotal of six units in a 24-hour period (i.e., a total of 900 mg ofibuprofen in a 24-hour period).

In another aspect, the number of unit oral dose compositions that can beadministered to the human can vary over a 2- or 3-day period, dependingon the duration and severity of acute pain and the subject's need forpain relief. The unit oral dose compositions can be administered to thehuman as multiple administrations as needed in each 24-hour period.Depending upon the dosage strength of ibuprofen in the unit oral dosecomposition, the total amount of ibuprofen taken over 3 days fortreatment of severe acute pain, for example, can be reduced from themaximum total amount of ibuprofen that can be administered (i.e., atotal of 3,600 mg). In one aspect, two unit oral dose compositions eachcontaining 200 mg of ibuprofen can be administered, followed by another2-unit dose of the unit dose composition 4 to 6 hours later, followed byanother 2-unit dose of the unit dose composition 4 to 6 hours later, fora total of six units (i.e.,1200 mg of ibuprofen) in the first 24-hourperiod; followed by a total of two units (i.e., 400 mg of ibuprofen) inthe second 24-hour period; followed by one unit (200 mg) in the third24-hour period, for a total of 1,800 mg of ibuprofen over 3 days (i.e.,50% less ibuprofen taken). In each instance, as discussed above, theunit oral dose compositions provide enhanced pain reduction in saidhuman who develops ibuprofen-induced heartburn when compared toibuprofen alone; as a result, the total amount of ibuprofen is reducedper day and over 3 days when said human uses the unit oral dosecompositions.

The unit oral dose compositions may be packaged in a variety of ways.Generally, an article for distribution includes a container thatcontains the unit oral dose composition in an appropriate form. Suitablecontainers are well known to those skilled in the art and includematerials such as bottles (plastic and glass), sachets, foil blisterpacks, and the like. The container may also include a tamper proofassemblage to prevent indiscreet access to the contents of the package.In addition, the container typically has deposited thereon a label thatdescribes the contents of the container and any appropriate warnings orinstructions.

The unit oral dose compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage forms. Thepack may for example comprise metal or plastic foil, such as a blisterpack. The pack or dispenser device may be accompanied by instructionsfor administration. The pack or dispenser may also be accompanied with anotice associated with the container in form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchnotice, for example, may be the labeling approved by the U.S. Food andDrug Administration for non-prescription drugs, or the approved productinsert. Pharmaceutical compositions comprising a disclosed compoundformulated in a compatible pharmaceutical carrier may also be prepared,placed in an appropriate container, and labeled for treatment of anindicated condition.

Aspects

Aspect 1. A method for reducing the severity of heartburn and/or therisk of the occurrence of heartburn in a human in need of takingibuprofen for the treatment of acute pain wherein the human is notexperiencing heartburn prior to the oral administration of the unit oraldose composition comprising orally administering to the human of a unitoral dose composition comprising (i) ibuprofen at a dosage from about 50mg to about 400 mg per unit oral dose composition and (ii) famotidine ata dosage from about 3 mg to about 20 mg per unit oral dose composition,wherein the dissolution rate of famotidine in the unit oral dosecomposition in said human at a specified time within 45 minutes ofadministration of said unit oral dose composition to said human isgreater than the dissolution rate of ibuprofen in the unit oral dosecomposition in said human at the same specified time.

Aspect 2. The method of Aspect 1, wherein the famotidine in the unitoral dose composition has a dissolution rate that is about 10% to about30% greater than the dissolution rate of ibuprofen at about 5 minutes,at about 10 minutes, at about 15 minutes, at about 20 minutes, at about30 minutes, or at 45 minutes after administration of the unit oral dosecomposition to the human.

Aspect 3. The method of Aspect 1, wherein the famotidine in the unitoral dose composition has a dissolution rate at about 10 minutes afteradministration of said unit oral dose composition to said human that isabout 5 minutes to less than 10 minutes earlier than the time requiredfor ibuprofen in said unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.

Aspect 4. The method of Aspect 1, wherein the famotidine in the unitoral dose composition has a dissolution rate at about 15 minutes afteradministration of said unit oral dose composition to said human that isabout 5 minutes to about 10 minutes earlier than the time required foribuprofen in said unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.

Aspect 5. The method of Aspect 1, wherein the famotidine in the unitoral dose composition has a dissolution rate at about 20 minutes afteradministration of said unit oral dose composition to said human that isabout 5 minutes to about 15 minutes earlier than the time required foribuprofen in said unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.

Aspect 6. The method of Aspect 1, wherein the famotidine in the unitoral dose composition has a dissolution rate at about 30 minutes afteradministration of said unit oral dose composition to said human that isabout 5 minutes to about 25 minutes earlier than the time required foribuprofen in said unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.

Aspect 7. The method of Aspect 1, wherein the famotidine in the unitoral dose composition has a dissolution rate at about 45 minutes afteradministration of said unit oral dose composition to said human that isabout 5 minutes to about 40 minutes earlier than the time required foribuprofen in said unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.

Aspect 8. The method of Aspect 1, wherein the unit oral dose compositioncomprises a bi-layer tablet comprising a first layer of famotidine andthe second layer comprising ibuprofen, wherein the famotidine comprisesmicroparticles, nanoparticles, or a combination thereof.

Aspect 9. The method of any one of Aspects 1-8, wherein the unit oraldose composition comprises a core comprising ibuprofen surrounded by alayer of famotidine, wherein the famotidine comprises microparticles,nanoparticles, or a combination thereof.

Aspect 10. The method of Aspect 8 or 9, wherein the famotidine has anaverage particle diameter of from about 1 micrometer to about 1,000micrometers.

Aspect 11. The method of Aspect 8 or 9, wherein the famotidine has anaverage particle diameter of from about 10 nanometers to about 1,000nanometers.

Aspect 12. The method of any one of Aspects 1-11, wherein the unit oraldose composition does not include a release-delaying agent or an entericcoating.

Aspect 13. The method of any one of Aspects 1-12, wherein the unit dosecomposition provides reduction of heartburn severity and/or reduction ofthe risk of the occurrence of heartburn in said human when compared tothe oral administration to said human of the same oral dosage strengthof said ibuprofen in the absence of said famotidine.

Aspect 14. The method of any one of Aspects 1-12, wherein the unit dosecomposition provides reduction of heartburn severity in said human whencompared to the oral administration of the same oral dosage strength ofsaid famotidine following heartburn induced by the same oral dosagestrength of ibuprofen administered to said human.

Aspect 15. The method of any one of Aspects 1-14, wherein the acute paincomprises acute pain of inflammation, acute pain or stiffness ofrheumatic or arthritic conditions, minor pain of arthritis, acute jointand body pains, dysmenorrhea (period pain), acute muscular aches andstrains, acute pain of ligamentous sprains, acute backache, minor achesand pains due to the common cold, minor aches and pains due to fever,acute headache, acute pain of minor surgery, acute toothache, occasionalsleeplessness when associated with minor aches and pains, or anycombination thereof.

Aspect 16. The method of any one of Aspects 1-15, wherein said unit oraldose composition provides enhanced pain reduction in said human whencompared to the oral administration to said human of the same dosagestrength of said ibuprofen in the absence of said famotidine.

Aspect 17. The method of any one of Aspects 1-15, wherein said unit oraldose composition further provides enhanced fever reduction in said humanwhen compared to the administration to said human of the same dosagestrength of said ibuprofen in the absence of said famotidine.

Aspect 18. The method of any one of Aspects 1-17, wherein ibuprofen isfrom about 150 mg to about 400 mg per unit oral dose composition.

Aspect 19. The method of any one of Aspects 1-17, wherein ibuprofen isabout 200 mg per unit oral dose composition.

Aspect 20. The method of any one of Aspects 1-17, wherein famotidine isfrom about 3 mg to about 20 mg per unit oral dose composition.

Aspect 21. The method of any one of Aspects 1-17, wherein famotidine isabout 10 mg per unit oral dose composition.

Aspect 22. The method of any one of Aspects 1-17, wherein famotidine isabout 6.67 mg or about 13.33 mg per unit oral dose composition.

Aspect 23. The method of any one of Aspects 1-17, wherein ibuprofen isfrom about 150 mg to about 400 mg per unit oral dose composition andfamotidine is from about 3 mg to about 20 mg per unit oral dosecomposition.

Aspect 24. The method of any one of Aspects 1-17, wherein ibuprofen isabout 200 mg per unit oral dose composition and famotidine is from about3 mg to about 20 mg per unit oral dose composition.

Aspect 25. The method of any one of Aspects 1-17, wherein ibuprofen isfrom about 150 mg to about 400 mg per unit oral dose composition andfamotidine is about 3.33 mg or about 13.33 mg per unit oral dosecomposition.

Aspect 26. The method of any one of Aspects 1-17, wherein ibuprofen isabout 250 mg per unit oral dose composition and famotidine is from about10 mg to about 13.33 mg per unit oral dose composition.

Aspect 27. The method of any one of Aspects 1-26, wherein the unit oraldose composition further comprises acetaminophen at a dosage of about 50mg to about 500 mg.

Aspect 28. The method of any one of Aspects 1-27, wherein the unit oraldose composition further comprises diphenhydramine HCl or citrate at adosage of about 5 mg to about 50 mg.

Aspect 29. A unit oral dose composition comprising (i) ibuprofen at adosage from about 50 mg to about 400 mg per unit oral dose compositionand (ii) famotidine at a dosage from about 3 mg to about 20 mg per unitoral dose composition, wherein the dissolution rate of famotidine in theunit oral dose composition in said human at a specified time within 45minutes of administration of said unit oral dose composition to saidhuman is greater than the dissolution rate of ibuprofen in the unit oraldose composition in said human at the same specified time.

Aspect 30. The unit oral dose composition of Aspect 29, wherein thefamotidine in the unit oral dose composition has a dissolution rate thatis about 10% to about 30% greater than the dissolution rate of ibuprofenat about 5 minutes, at about 10 minutes, at about 15 minutes, at about20 minutes, at about 30 minutes, or at 45 minutes after administrationof the unit oral dose composition to the human.

Aspect 31. The unit oral dose composition of Aspect 29, wherein thefamotidine in the unit oral dose composition has a dissolution rate atabout 10 minutes after administration of said unit oral dose compositionto said human that is about 5 minutes to less than 10 minutes earlierthan the time required for ibuprofen in said unit oral dose compositionto achieve the same dissolution rate after administration of the unitoral dose composition to the human.

Aspect 32. The unit oral dose composition of Aspect 29, wherein thefamotidine in the unit oral dose composition has a dissolution rate atabout 15 minutes after administration of said unit oral dose compositionto said human that is about 5 minutes to about 10 minutes earlier thanthe time required for ibuprofen in said unit oral dose composition toachieve the same dissolution rate after administration of the unit oraldose composition to the human.

Aspect 33. The unit oral dose composition of Aspect 29, wherein thefamotidine in the unit oral dose composition has a dissolution rate atabout 20 minutes after administration of said unit oral dose compositionto said human that is about 5 minutes to about 15 minutes earlier thanthe time required for ibuprofen in said unit oral dose composition toachieve the same dissolution rate after administration of the unit oraldose composition to the human.

Aspect 34. The unit oral dose composition of Aspect 29, wherein thefamotidine in the unit oral dose composition has a dissolution rate atabout 30 minutes after administration of said unit oral dose compositionto said human that is about 5 minutes to about 25 minutes earlier thanthe time required for ibuprofen in said unit oral dose composition toachieve the same dissolution rate after administration of the unit oraldose composition to the human.

Aspect 35. The unit oral dose composition of Aspect 29, wherein thefamotidine in the unit oral dose composition has a dissolution rate atabout 45 minutes after administration of said unit oral dose compositionto said human that is about 5 minutes to about 40 minutes earlier thanthe time required for ibuprofen in said unit oral dose composition toachieve the same dissolution rate after administration of the unit oraldose composition to the human.

Aspect 36. The unit oral dose composition of any one of Aspects 29-35,wherein the unit oral dose composition comprises a bi-layer tabletcomprising a first layer of famotidine and the second layer comprisingibuprofen, wherein the famotidine comprises microparticles,nanoparticles, or a combination thereof.

Aspect 37. The unit oral dose composition of any one of Aspects 29-35,wherein the unit oral dose composition comprises a core comprisingibuprofen surrounded by a layer of famotidine, wherein the famotidinecomprises microparticles, nanoparticles, or a combination thereof.

Aspect 38. The unit oral dose composition of Aspect 37, wherein thefamotidine has an average particle diameter of from about 1 micrometerto about 1,000 micrometers.

Aspect 39. The unit oral dose composition of Aspect 37, wherein thefamotidine has an average particle diameter of from about 10 nanometersto about 1,000 nanometers.

Aspect 40. The unit oral dose composition of any one of Aspects 29-39,wherein the unit oral dose composition does not include arelease-delaying agent or an enteric coating.

Aspect 41. The unit oral dose composition of any one of Aspects 29-40,wherein ibuprofen is from about 150 mg to about 400 mg per unit oraldose composition.

Aspect 42. The unit oral dose composition of any one of Aspects 29-40,wherein ibuprofen is about 200 mg per unit oral dose composition.

Aspect 43. The unit oral dose composition of any one of Aspects 29-40,wherein famotidine is from about 3 mg to about 20 mg per unit oral dosecomposition.

Aspect 44. The unit oral dose composition of any one of Aspects 29-40,wherein famotidine is about 10 mg per unit oral dose composition.

Aspect 45. The unit oral dose composition of any one of Aspects 29-40,wherein famotidine is about 6.67 mg or about 13.33 mg per unit oral dosecomposition.

Aspect 46. The unit oral dose composition of any one of Aspects 29-40,wherein ibuprofen is from about 150 mg to about 400 mg per unit oraldose composition and famotidine is from about 3 mg to about 20 mg perunit oral dose composition.

Aspect 47. The unit oral dose composition of any one of Aspects 29-40,wherein ibuprofen is about 200 mg per unit oral dose composition andfamotidine is from about 3 mg to about 20 mg per unit oral dosecomposition.

Aspect 48. The unit oral dose composition of any one of Aspects 29-40,wherein ibuprofen is from about 150 mg to about 400 mg per unit oraldose composition and famotidine is about 3.33 mg or about 13.33 mg perunit oral dose composition.

Aspect 49. The unit oral dose composition of any one of Aspects 29-40,wherein ibuprofen is about 250 mg per unit oral dose composition andfamotidine is from about 10 mg to about 13.33 mg per unit oral dosecomposition.

Aspect 50. The unit oral dose composition of any one of Aspects 29-49,wherein the unit oral dose composition further comprises acetaminophenat a dosage of about 50 mg to about 500 mg.

Aspect 51. The unit oral dose composition of any one of Aspects 29-50,wherein the unit oral dose composition further comprises diphenhydramineHCl or citrate at a dosage of about 5 mg to about 50 mg.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the compounds, compositions and methods described herein.

Various modifications and variations can be made to the compounds,compositions and methods described herein. Other aspects of thecompounds, compositions and methods described herein will be apparentfrom consideration of the specification and practice of the compounds,compositions and methods disclosed herein. It is intended that thespecification and examples be considered as exemplary.

1. A method for reducing the severity of heartburn in a human takingibuprofen for the treatment of acute pain, wherein the human is notexperiencing heartburn prior to the oral administration of a unit oraldose composition comprising (i) ibuprofen at a dosage from about 50 mgto about 400 mg per unit oral dose composition and (ii) famotidine at adosage from about 3 mg to about 20 mg per unit oral dose composition,wherein the unit oral dose composition does not include arelease-delaying agent or an enteric coating; and wherein the famotidinein the unit oral dose composition has a dissolution rate that is about10% to about 30% greater than the dissolution rate of ibuprofen at about5 minutes, at about 10 minutes, at about 15 minutes, at about 20minutes, at about 30 minutes, or at 45 minutes after administration ofthe unit oral dose composition to the human, the method comprisingorally administering to the human the unit oral dose composition.
 2. Themethod of claim 1, wherein the unit oral dose composition comprises acore comprising ibuprofen surrounded by a layer comprising famotidine.3. The method of claim 2, wherein the layer of famotidine has athickness of from about 10 μm to about 500 μm.
 4. The method of claim 1,wherein the unit oral dose composition does not include a barrier layer.5. The method of claim 1, wherein the average particle size of ibuprofenis greater than average particle size of famotidine.
 6. The method ofclaim 1, wherein famotidine is in the form of microparticles,nanoparticles, or a combination thereof, wherein the average particlesize of ibuprofen is greater than average particle size of famotidine.7. The method of claim 1, wherein famotidine and ibuprofen are in theform of microparticles, nanoparticles, or a combination thereof.
 8. Themethod of claim 1, wherein the unit dose composition is a tablet havingthe shape of a disk, sphere, rhomboid, or oval or the unit dosecomposition is a caplet.
 9. The method of claim 1, wherein thefamotidine in the unit oral dose composition has a dissolution rate atabout 10 minutes after administration of the unit oral dose compositionto the human that is about 5 minutes to less than 10 minutes earlierthan the time required for ibuprofen in the unit oral dose compositionto achieve the same dissolution rate after administration of the unitoral dose composition to the human.
 10. The method of claim 1, whereinthe famotidine in the unit oral dose composition has a dissolution rateat about 15 minutes after administration of the unit oral dosecomposition to the human that is about 5 minutes to about 10 minutesearlier than the time required for ibuprofen in the unit oral dosecomposition to achieve the same dissolution rate after administration ofthe unit oral dose composition to the human.
 11. The method of claim 1,wherein the famotidine in the unit oral dose composition has adissolution rate at about 20 minutes after administration of the unitoral dose composition to the human that is about 5 minutes to about 15minutes earlier than the time required for ibuprofen in the unit oraldose composition to achieve the same dissolution rate afteradministration of the unit oral dose composition to the human.
 12. Themethod of claim 1, wherein the famotidine in the unit oral dosecomposition has a dissolution rate at about 30 minutes afteradministration of the unit oral dose composition to the human that isabout 5 minutes to about 25 minutes earlier than the time required foribuprofen in the unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.
 13. The method of claim 1, wherein the famotidine in theunit oral dose composition has a dissolution rate at about 45 minutesafter administration of the unit oral dose composition to the human thatis about 5 minutes to about 40 minutes earlier than the time requiredfor ibuprofen in the unit oral dose composition to achieve the samedissolution rate after administration of the unit oral dose compositionto the human.
 14. The method of claim 1, wherein the unit dosecomposition provides reduction of heartburn severity in the human whencompared to the oral administration to the human of the same oral dosageof ibuprofen in the absence of famotidine.
 15. The method of claim 1,wherein the unit dose composition provides reduction of heartburnseverity in the human when compared to the oral administration of thesame oral dosage of famotidine following heartburn induced by the sameoral dosage of ibuprofen administered to the human.
 16. The method ofclaim 1, wherein the acute pain comprises acute pain is selected fromthe group consisting of inflammation, acute pain or stiffness ofrheumatic or arthritic conditions, minor pain of arthritis, acute jointand body pains, acute muscular aches and strains, dysmenorrhea, acutepain of ligamentous sprains, acute backache, minor aches and pains dueto the common cold, sore throat, minor aches and pains due to fever,acute headache, acute pain of minor surgery, acute toothache, occasionalsleeplessness when associated with minor aches and pains, and anycombination thereof.
 17. The method of claim 1, wherein the unit oraldose composition provides enhanced acute pain reduction in the humanwhen compared to the oral administration to the human of the same dosageof ibuprofen in the absence of famotidine.
 18. The method of claim 1,wherein the unit oral dose composition further provides enhanced feverreduction in the human when compared to the administration to the humanof the same dosage of ibuprofen in the absence of famotidine.
 19. Themethod of claim 1, wherein ibuprofen is from about 150 mg to about 400mg per unit oral dose composition.
 20. The method of claim 1, whereinibuprofen is about 200 mg per unit oral dose composition.
 21. The methodof claim 1, wherein famotidine is about 10 mg per unit oral dosecomposition.
 22. The method of claim 1, wherein famotidine is about 6.67mg or about 13.33 mg per unit oral dose composition.
 23. The method ofclaim 1, wherein ibuprofen is from about 150 mg to about 400 mg per unitoral dose composition and famotidine is about 3.33 mg or about 13.33 mgper unit oral dose composition.
 24. The method of claim 1, whereinibuprofen is about 250 mg per unit oral dose composition and famotidineis from about 10 mg to about 13.33 mg per unit oral dose composition.25. The method of claim 1, wherein the unit oral dose compositionfurther comprises acetaminophen at a dosage of about 50 mg to about 500mg.
 26. The method of claim 1, wherein the unit oral dose compositionfurther comprises diphenhydramine HCl or citrate at a dosage of about 5mg to about 50 mg.
 27. A method for reducing the occurrence of heartburnin a human taking ibuprofen for the treatment of acute pain, wherein thehuman is not experiencing heartburn prior to the oral administration ofa unit oral dose composition comprising (i) ibuprofen at a dosage fromabout 50 mg to about 400 mg per unit oral dose composition and (ii)famotidine at a dosage from about 3 mg to about 20 mg per unit oral dosecomposition, wherein the unit oral dose composition does not include arelease-delaying agent or an enteric coating; and wherein the famotidinein the unit oral dose composition has a dissolution rate that is about10% to about 30% greater than the dissolution rate of ibuprofen at about5 minutes, at about 10 minutes, at about 15 minutes, at about 20minutes, at about 30 minutes, or at 45 minutes after administration ofthe unit oral dose composition to the human, the method comprisingorally administering to the human the unit oral dose composition.
 28. Aunit oral dose composition comprising (i) ibuprofen at a dosage fromabout 50 mg to about 400 mg per unit oral dose composition and (ii)famotidine at a dosage from about 3 mg to about 20 mg per unit oral dosecomposition, wherein the unit oral dose composition does not include arelease-delaying agent or an enteric coating; and wherein the famotidinein the unit oral dose composition has a dissolution rate that is about10% to about 30% greater than the dissolution rate of ibuprofen at about5 minutes, at about 10 minutes, at about 15 minutes, at about 20minutes, at about 30 minutes, or at 45 minutes after administration ofthe unit oral dose composition to the human.
 29. The unit oral dosecomposition of claim 28, wherein the unit oral dose compositioncomprises a core comprising ibuprofen surrounded by a layer comprisingfamotidine.
 30. The unit oral dose composition of claim 29, wherein thelayer of famotidine has a thickness of from about 10 μm to about 500 μm.31. The unit oral dose composition of claim 28, wherein the unit oraldose composition does not include a barrier layer.
 32. The unit oraldose composition of claim 28, wherein the average particle size ofibuprofen is greater than average particle size of famotidine.
 33. Theunit oral dose composition of claim 28, wherein famotidine is in theform of microparticles, nanoparticles, or a combination thereof, whereinthe average particle size of ibuprofen is greater than average particlesize of famotidine.
 34. The unit oral dose composition of claim 28,wherein famotidine and ibuprofen are in the form of microparticles,nanoparticles, or a combination thereof.
 35. The unit oral dosecomposition of claim 28, wherein the unit dose composition is a tablethaving the shape of a disk, sphere, rhomboid, or oval or the unit dosecomposition is a caplet.
 36. The unit oral dose composition of claim 28,wherein ibuprofen is from about 150 mg to about 400 mg per unit oraldose composition.
 37. The unit oral dose composition of claim 28,wherein ibuprofen is about 200 mg per unit oral dose composition. 38.The unit oral dose composition of claim 28, wherein famotidine is about10 mg per unit oral dose composition.
 39. The unit oral dose compositionof claim 28, wherein famotidine is about 6.67 mg or about 13.33 mg perunit oral dose composition.
 40. The unit oral dose composition of claim28, wherein ibuprofen is from about 150 mg to about 400 mg per unit oraldose composition and famotidine is about 3.33 mg or about 13.33 mg perunit oral dose composition.
 41. The unit oral dose composition of claim28, wherein ibuprofen is about 250 mg per unit oral dose composition andfamotidine is from about 10 mg to about 13.33 mg per unit oral dosecomposition.
 42. The unit oral dose composition of claim 28, wherein theunit oral dose composition further comprises acetaminophen at a dosageof about 50 mg to about 500 mg.
 43. The unit oral dose composition ofclaim 28, wherein the unit oral dose composition further comprisesdiphenhydramine HCl or citrate at a dosage of about 5 mg to about 50 mg.